Rheumatoid arthritis

Disease ID:831
Name:Rheumatoid arthritis
Associated with:19 targets
11 immuno-relevant targets
123 immuno-relevant ligands
Database Links
Disease Ontology: DOID:7148
OMIM: 180300

Targets

C5a1 receptor
Role:  In a rat model of antigen-induced monoarticular rheumatoid arthritis, oral administration of the C5aR antagonist PMX53 reduced oedema, inflammatory infiltrate and interarticular cytokines. However, in a double-blind, placebo controlled clinical trial, orally-administered PMX53 did not reduce synovial inflammation in rheumatoid arthritis patients.
References:  125,133
CXCR5
References:  106
CCRL2
Role:  CCRL2 expression is up-regulated in synovial neutrophils of rheumatoid arthritis patients. Inflammatory products present in the synovial fluid activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of rheumatoid arthritis
References:  5,40
chemerin receptor 1
References:  32
FZD5
References:  107
BLT1 receptor
Comments:  The expression of LTB4R (BLT1) and LTB4R2 (BLT2) mRNA is elevated in synovial tissues of RA patients compared to OA patients., with LTB4R2 > LTB4R. LTB4R2 is the principal mediator of leukotriene B4 effects in RA synovial tissues.
References:  17,45,51,62,78,104,109
Ligand interactions: 
Ligand Comments
CP-195543
CP-195543 was a Phase 2 clinical candidate for RA (see NCT00424294). Development was discontinued due to its poor tolerability profile and high discon ...
BLT2 receptor
Comments:  The expression of LTB4R (BLT1) and LTB4R2 (BLT2) mRNA is elevated in synovial tissues of RA patients compared to OA patients., with LTB4R2 > LTB4R. LTB4R2 is the principal mediator of leukotriene B4 effects in RA synovial tissues.
Ligand interactions: 
Ligand Comments
CP-195543
CP-195543 was a Phase 2 clinical candidate for RA (see NCT00424294). Development was discontinued due to its poor tolerability profile and high discon ...
MMP1
Comments:  Serum level of MMP1 correlates with disease activity in RA.
Ligand interactions: 
Ligand Comments
cipemastat
An MMP1 clinical candidate which failed Phase 1 clinical trial in RA.
MMP3
Comments:  Serum level of MMP3 correlates with disease activity in RA, and is used as a biomarker for predicting bone and cartilage damage and evaluating therapeutic efficacy.
MMP14
Comments:  MMP14 (also called MT1-MMP) is highly expressed in fibroblast-like synoviocytes and macrophages from patients with RA, and is reckoned to be one of the main MMPs involved in degradation of collagenous cartilage matrix
ADAMTS4
Comments:  ADAMTS4 is involved in RA pathogenesis.
ADAMTS5
Comments:  ADAMTS5 is involved in RA pathogenesis.
NLRC5
Comments:  A study by Liu et al. (2017) found that NLRC5 is upregulated in synovial tissues and cells of AA animal models, NLRC5 silencing inhibits inflammatory cytokine expression and cell proliferation of fibroblast-like synoviocytes, and that NLRC5 expression inducescell proliferation via NF-κB activation and signaling.
CIITA
NLRP1
BAFF receptor
Comments:  Molecular target for RA- see NCT02675803 which was designed to evaluate clinical efficacy of anti-BAFF-R mAb VAY736 in RA patients.
Ligand interactions: 
Ligand Comments
BAFF
BAFF is a drug target for RA.
CD80
Comments:  CD80 is a primary target of the ligand abatacept, which is clinically approved for the treatment of rheumatoid arthritis.
Ligand interactions: 
Ligand Comments
abatacept
Approved drug for RA.
CD86
Comments:  CD86 is a primary target of the ligand abatacept, which is clinically approved for the treatment of rheumatoid arthritis.
Ligand interactions: 
Ligand Comments
abatacept
Approved drug for RA.
peptidyl arginine deiminase 4

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
piclidenoson
Immuno Disease Comments: Clinical candidate for RA (Phase 2 NCT01034306).
Clinical Use: Piclidenoson (CF101) is being evaluated in a number of clinical trials, as a potential therapy for several autoimmune-inflammatory disorders (rheumatoid arthritis, Phase III, NCT02647762 [123]; plaque psoriasis, Phase II [24]; uveitis Phase II) and glaucoma (Phase II, NCT01033422 [37]). | View clinical data
adalimumab
Immuno Disease Comments: Anti-TNFα monoclonal antibody therapy approved for RA
Clinical Use: Used in the management of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and plaque psoriasis.
In 2015 both the EMA and the FDA approved the use of adalimumab as a treatment for hidradenitis suppurativa, a chronic skin disease that causes abscesses and scarring on the skin.
In July 2016, the FDA expanded adalimumab approval as the first non-corticosteroid drug available for use as a treatment for non-infectious intermediate, posterior and panuveitis (forms of autoimmune-driven inflammation of the uvea)- results from Phase 3 clinical trial NCT01138657 are published in [57]. | View clinical data
doramapimod
Immuno Disease Comments: Phase 2 clinical candidate for RA.
Clinical Use: Doramapimod (as research code BIRB 796) has been assessed in Phase II clinical trials for plaque-type psoriasis and rheumatoid arthritis (RA). Additional trials for RA and Crohn's disease were terminated. Development of the compound has not progressed beyond Phase II. | View clinical data
Bioactivity Comments: Doramapimod shows moderate selectivity for the p38α, -β and -γ isozymes compared to p38δ [85]. A Kd value of 0.1nM is reported in [96], but the authors do not specify subtype identity. In a screening panel of kinases, doramapimod inhibited many kinases with IC50 values <100nM (see Supplementary Information attached to [85]). | View biological activity
tamatinib
Immuno Disease Comments: This is the active metaboloite of fostamatinib and may have clinical utility in RA.
Clinical Use: Tamatinib is a potential drug for treatment of the inflammation associated with and causing bronchial asthma resulting from allergen-induced airway hyperresponsiveness (AHR). The compound may have beneficial effects in additional inflammatory conditions, such as rheumatoid arthritis and other autoimmune conditions. | View clinical data
Bioactivity Comments: Autophosphorylation of FLT3 is inhibited by tamatinib [11]. Inhibition of RET by tamatinib is thought to be responsible for renal and ureteric agenesis observed in developmental toxicity tests carried out in rats and rabbits [20]. | View biological activity
IL-6
Immuno Disease Comments: IL-6 is known to drive arthritic inflammation and bone destruction in RA. mAbs against both the IL-6 ligand and its receptor (IL-6R) are now approved for use in the clinic, and accumulating evidence suggests that targeting of IL-6 can be the best treatment option for RA. In light of this, development of new monoclonal antibodies targeting the IL-6/IL-6R pathway is continuing.
infliximab
Immuno Disease Comments: Used in combination with methotrexate to reduce production of anti-infliximab antibodies. However, if infliximab is rendered ineffective, other anti-TNFα agents can be used as an alternative therapy.
Clinical Use: Used in the management of rheumatoid arthritis (in combination with ), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease [119] and ulcerative colitis. | View clinical data
Bioactivity Comments: Infliximab has been reported to induce an anti-chimeric antibody response in almost 15% of Crohn's disease patients (47 tested) [102]. This indicates that as predicited, humans can mount an immune response to whole murine variable domains, and is the underlying rationale promoting the development of clinical antibodies with variable domains with more human character (i.e. humanised or fully human monoclonal developments). | View biological activity
sarilumab
Immuno Disease Comments: FDA approved therapeutic for RA (May 2017).
Clinical Use: Sarilumab was granted FDA approval as a treatment for moderate to severe active RA in May 2017 (with EMA approval granted in June 2017), following evaluation in several clinical trials, either as a monotherapy (eg NCT02121210) or in combination with other drugs such as , , and .
Click here to link to ClinicalTrials.gov's listing of Phase III sarilumab trials. A Phase II study for non-infectious uveitis (NCT01900431) has been completed, whereas a Phase II extension study (NCT01118728) for ankylosing spondylitis was terminated. | View clinical data
etanercept
Immuno Disease Comments: Approved drug for severe active RA.
Clinical Use: Used to treat severe active rheumatoid arthritis in adults, severe juvenile idiopathic arthritis, ankylosing spondylitis, and severe plaque psoriasis. | View clinical data
CR6086
Immuno Disease Comments: CR6086 is a Phase 2 clinical candidate for RA- see NCT03163966
Clinical Use: A proof-of-concept clinical trial evaluating CR6086 plus in RA patients with early stage disease and who are DMARD-naive is underway- see NCT03163966. | View clinical data
Bioactivity Comments: CR6086 at concentrations up to 10 μM showed no significant binding affinities for the other eicosanoid receptors and did not inhibit COX enzyme activities [14]. | View biological activity
remtolumab
Immuno Disease Comments: Phase 2 clinical candidate for RA- see NCT02433340
Clinical Use: Remtolumab has reached Phase 2 clinical trial for rheumatoid arthritis and psoriatic arthritis. | View clinical data
maraviroc
Immuno Disease Comments: Maraviroc-induced CCR5 blockade failed to show clinical efficacy in RA clinical trial.
Clinical Use: Maraviroc is approved for use in combination antiretroviral treatment of patients infected with CCR5-tropic HIV-1 virus.

Maraviroc-induced CCR5 blockade was investigated for action in treating rheumatoid arthritis, but with discouraging clinical trial results. Other CCR5 antagonists ( and ) have also proven ineffective in RA clinical trials [115] | View clinical data
Bioactivity Comments: Maraviroc has been described as a negative allosteric modulator of CCR5 [19]. | View biological activity
ancriviroc
Immuno Disease Comments: Ancriviroc-induced CCR5 blockade failed to show clinical efficacy in RA.
indomethacin
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Indomethacin is used widely for various inflammatory conditions, for which the drug's analgesic and antipyretic properties are beneficial. Such conditions include rheumatoid and osteoarthritis, ankylosing spondylitis, bursitis and/or tendinitis and acute gouty arthritis. | View clinical data
gimsilumab
Immuno Disease Comments: Phase 1 clinical candidate for RA. A single-dose of 10 mg/kg produced a clinically meaningful effect, evaluated as a decreased disease activity score based on C-reactive protein, 5 days post treatment.
Clinical Use: Phase 1 study (NCT01357759) in healthy volunteers and patients with rheumatoid arthritis has been completed. | View clinical data
acalabrutinib
Immuno Disease Comments: Phase 2 clinical trial in RA completed (NCT02387762)
Clinical Use: Having already received FDA Orphan Drug Designation and Breakthrough Therapy Designation for mantle cell lymphoma (MCL: a rare and fast-growing type of non-Hodgkin lymphoma), in August 2017 the FDA granted priority review for acalabrutinib's New Drug Application (NDA), based on results from a Phase 2 study in relapsed/refractory MCL (NCT02213926). This resulted in full FDA approval in October 2017 (link to FDA announcement). This approval is for the treatment of MCL patients who have received at least one prior therapy.

Additional trials are evaluating acalabrutinib in other cancers. For example: Phase 3 trial in patients with chronic lymphocytic leukemia (CLL)- see NCT02475681 and NCT02477696; Phase 2 clinical trials to assess acalabrutinib's efficacy against other B cell malignancies and a variety of solid tumours (such as bladder, prostate and non-small cell lung cancers). In total, more than 25 acalabrutinib clinical trials are underway or have completed. For a list of all registered trials, link here to ClinicalTrials.gov. Phase 1/2 trial results in patients with CLL are reported by Byrd et al. (2015) [12].

In the European Union, the EMA has granted acalabrutinib orphan designation for three rare diseases (as of 2016): chronic lymphocytic leukaemia / small lymphocytic lymphoma, lymphoplasmacytic lymphoma and mantle cell lymphoma. | View clinical data
Bioactivity Comments: Acalabrutinib has improved selectivity, pharmacologic features (rapid oral absorption, favourable plasma exposure and a short half-life for example) and in vivo target coverage compared to the first generation BTK inhibitor, [12,134]. The IC50 values in the table below are for kinases that contain a cysteine residue aligning with Cysteine-481 in BTK (with exception of LYN). Unlike ibrutinib, acalabrutinib is devoid of activity across the SRC family kinases (IC50s > 1000 nM) [12]. | View biological activity
ozoralizumab
Immuno Disease Comments: Ozoralizumab has completed proof-of-concept Phase II clinical trial in RA (NCT00959036- in patients on a background of methotrexate)
Bioactivity Comments: Ozoralizumab binds serum albumin, in addition to TNFα, an action that increases its in vivo half-life [66]. | View biological activity
fosdagrocorat 112
Immuno Disease Comments: Phase 2 clinical trial in RA (NCT00938587) has been completed.
Clinical Use: Results of a Phase 2 clinical trial evaluating fosdagrocorat in patients with rheumatoid arthritis (RA) have been published [112], which report positive outcomes with regards to efficacy in improving RA signs and symptoms, with manageable adverse events. The efficacy of fosdagrocorat (10 and 15 mg/day) was equivalent to 10 mg/day prednisone, whereas its impact on biomarkers for bone formation and resorption, and plasma glucose were comparable to a lower prednisone dose of 5 mg/day. | View clinical data
evobrutinib
Immuno Disease Comments: Phase 2 clinical candidate for RA- see NCT03233230
Clinical Use: Evobrutinib is being evaluated in Phase 2 clinical trials for rheumatoid arthritis, systemic lupus erythematosus and relapsing-remitting multiple sclerosis. A full list of evobrutinib trials registered with ClinicalTrials.gov is available by clicking here. | View clinical data
PF-06650833 68
Immuno Disease Comments: Phase 2 clinical candidate for RA- see NCT02996500.
Clinical Use: A Phase 2 clinical trial evaluating PF-06650833 in patients with rheumatoid arthritis (RA) and an inadequate response to (NCT02996500) is underway. In this study PF-06650833 is being compared to the JAK3 kinase inhibitor , which is an approved RA drug. | View clinical data
Bioactivity Comments: PF-06650833 inhibits TLR7/8 agonist R848-induced TNFα production in human peripheral blood mononuclear cells with an IC50 of 2nM [68]. Further preclinical results detailing the pharmacokinetic and ADME profiles of PF-06650833 are reported in [68]. In a kinome selectivity profile 200nM PF-06650833 completely inhibited IRAK4 activity, and inhibited the additional kinases IRAK1, MNK2, LRRK2, CLK4, and CK1γ1 by > 70%. In a more physiologically relevant screen, other than IRAK4, 200nM PF-06650833 inhibited only CK1γ2, IRAK3/M, PIPK2C, and CK1δ/ε by > 50%. | View biological activity
Galapagos MAPKAPK5 inhibitor D 130
Immuno Disease Comments: Failed Phase 2 clinical candidate for methotrexate-refractory RA.
GW406381
Immuno Disease Comments: Phase 3 clinical candidate for RA- see NCT00113308.
Clinical Use: GW406381 has completed Phase 3 clinical evaluation in knee osteoarthritis [10], rheumatoid arthritis, and post-dental surgery pain (clinically meaningful analgesia was demnostrated in this acute pain setting, but time to onset was >1 hour) [124]. | View clinical data
Bioactivity Comments: GW406381 is almost 30000 times more potent at COX2 compared to COX1 [8]. | View biological activity
MK-0359
Immuno Disease Comments: Completed Phase 2 clinical evaluation in RA- see NCT00482417
Clinical Use: MK-0359 exhibited clinical efficacy in a Phase 2 study in asthma patients (NCT00482898), but caused gastrointestinal adverse effects [71]. It has completed Phase 2 studies in rheumatoid arthritis (NCT00482417) and chronic obstructive pulmonary disease (NCT00482235). | View clinical data
Bioactivity Comments: MK-0359 is active in vitro and in vivo [55]. It blocks LPS-induced TNF-α formation in whole blood assays with a potency similar to that exhibited by . Evidence suggest that majority of the anti-inflammatory effect of PDE4 inhibition is through PDE4B and PDE4D isozymes, and that PDE4D, as the major isoform in the brain responsible for emesis [100], is associated with the adverse gastrointestinal (GI) events associated with PDE4 inhibition. MK-0359 inhibits the hydrolysis of cAMP by PDE4A, 4B and 4D with similar potencies, which accounts for the adverse GI effects observed in clinical trial [71]. | View biological activity
baricitinib
Immuno Disease Comments: Approved drug for moderate to severe RA.
Clinical Use: The EMA granted baricitinib marketing authorisation in February 2017, for the treatment of rheumatoid arthritis (RA). This approval covered doses of either 2 or 4 mg. Phase 3 trial results reporting significant clinical improvement in patients who's symptoms had failed to respond to other disease-modifying antirheumatic drugs (DMARDs) were published in [41]. These are the results of the RA-BEACON study NCT01721044. FDA approval, as a once daily treatment for moderately-to-severely active RA, in patients with an inadequate response to one or more tumour necrosis factor (TNF) inhibitor therapies, was granted in June 2018, but only for the 2 mg dose. In both jurisdictions, baricitinib can be used as monotherapy, or in combination with or other non-biologic DMARDs. Use of baricitinib in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as and is not recommended. | View clinical data
Bioactivity Comments: Preclinical studies of baricitinib have shown it to be effective in rat models of rheumatoid arthritis [39].
A single patient with alopecia areata (AA) with comorbid CANDLE syndrome (a immunoproteasome-related disorder with a prominent interferon (IFN) signature, a disease feature shared with AA), recruited to a clinical trial testing baricitinib as a treatment for their CANDLE syndrome (NCT01724580) experienced significant hair regrowth [56]. Mechanistic assessment in a mouse AA model, confirmed that clinical improvement correlated with baricitinib-induced resolution of the IFN signature. Other JAK inhibitors such as and have also been reported to promote hair regrowth in AA in early stage trials [23,75,135]. | View biological activity
CFZ533
Immuno Disease Comments: Phase 1 clinical candidate for RA- see completed trial NCT02089087
Clinical Use: CFZ533 is being evaluated in clinical trials as a therapy for some autoimmune conditions and for preventing/reducing solid organ transplant rejection. Click here to link to ClinicalTrials.gov's full list of CFZ533 trials. | View clinical data
Bioactivity Comments: CFZ533 (mAb1) shows no agonist activity in an in vitro assay using isolated human PBMCs, blocks -mediated PBMC proliferation (IC50 58 ng/ml), inhibits CD40L-mediated TNF-α release from human monocyte derived dendritic cells (IC50 40 ng/ml), and has ADCC activity of < 1% (measuring specific lysis) [54]. | View biological activity
AZD9567
Immuno Disease Comments: Phase 2 clinical candidate for RA- see NCT03368235
Clinical Use: AZD9567 has reached Phase 2 clinical trial for rheumatoid arthritis in which it is being compared to (see NCT03368235). | View clinical data
Bioactivity Comments: In a cellular transactivation (TA) assay AZD9567 exhibits partial agonism (EC50 11nM, with agonist efficacy of 36%), and in the TA antagonist assay it has an IC50 of 160nM (antagonist efficacy of 56%) [98]. AZD9567 is highly selective for GR compared to the progesterone, mineralocorticoid, androgen and estrogen (α and β) receptors, as well as vs. a number of other proteins tested. Although AZD9567 is a partial agonist in transactivation assays, it mediates full GR translocation into the nucleus. Orally AZD9567 elicits potent anti-inflammatory effects in rat model of joint inflammation [98]. | View biological activity
CZ415 13
Immuno Disease Comments: CZ415 exhibits potent preclinical anti-inflammatory activity in vivo, and is under consideration for rheumatoid arthritis.
Bioactivity Comments: CZ415 is >1000-fold selective for mTOR over other lipid kinases from the same family (i.e. phosphatidylinositide 3-kinases (PI3K) α/&beta/γ/δ and DNA-dependent protein kinase (DNAPK)) [13]. CZ415 inhibits mTORC1- and mTORC2-dependent signalling in vitro (assessed as inhibition of phosphorylation of the downstream targets S6 ribosomal protein and protein kinase B respectively) with high potency. As a therapeutic lead, CZ415 has low hERG liability (IC50 48μM). | View biological activity
CH-4051
Immuno Disease Comments: CH-4501 completed Phase 2 trial in RA- see NCT01116141
Clinical Use: CH-4051 completed Phase 2 clinical trial in patients with rheumatoid arthritis (NCT01116141). | View clinical data
MK-0873
Immuno Disease Comments: Completed Phase 2 trial for RA- see NCT00132769
Clinical Use: MK-0873 has completed Phase 2 clinical evaluation in rheumatoid arthritis (NCT00132769), and Phase 1 as a topical agent for plaque psoriasis (NCT01235728). A Phase 2 trial in patients with chronic obstructive pulmonary disease (COPD) was terminated (NCT00132730). | View clinical data
Bioactivity Comments: MK-0873 inhibits LPS-induced production of TNF-α in human whole blood assays. Only the IC50 of MK-0873 vs. PDE4A is defined in [48], but the authors state less than a 5-fold difference in the IC50 values across the 4 PDE4 isozymes (4A, 4B, 4C and 4D). | View biological activity
PF-04905428
Immuno Disease Comments: Failed to show clinical efficacy in Phase 3 trial.
Clinical Use: A Phase III clinical trial in patients with rheumatoid arthritis (RA: NCT00628095) has been completed. Results showed PF-04905428 (CE-224,535) was not effective in treating RA [113]. | View clinical data
Bioactivity Comments: PF-04905428 was tested for its ability to inhibit lL-1β release from ATP-stimulated monocytes. This assay provides an IC50 of 1.3nM [114]. We have tagged P2X7 receptor as the primary molecular target based on details in [31] and [28], despite neither of these publications containing a bona fide affinity value for PF-04905428 binding.
The selectivity of PF-04905428 for the human P2X7 receptor precludes its evaluation in rodent disease models. | View biological activity
CCL2
Immuno Disease Comments: CCL2 is implicated in the pathogenesis of RA.
niflumic acid
Immuno Disease Comments: COX2 inhibition affords this drug anti-inflammatory activity, used clinically for the treatment of RA.
Clinical Use: Used in the treatment of rheumatoid arthritis. There is no information regarding approval for clinical use of this drug on the US FDA or European Medicines Agency websites. Individual national agencies may have granted marketing authorisation. | View clinical data
Bioactivity Comments: We have been unable to find affinity data for this drug (at the human targets) to substantiate its MMOA. | View biological activity
mefenamic acid
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, inflammation, fever and pain. | View clinical data
ibuprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Ibuprofen is used widely for its analgesic and antipyretic actions. | View clinical data
diclofenac
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Diclofenac is used to treat pain or inflammation caused by osteoarthritis and rheumatoid arthritis, but is also used to treat other conditions which benefit from the analgesic and antipyretic properties of NSAIDs. | View clinical data
prednisolone
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including RA.
Clinical Use: This drug used as an antiinflammatory or immunosuppressive agent and is indicated for the treatment of various inflammatory pathologies, including acute asthma, suppression of inflammatory and allergic disorders, ulcerative colitis, Crohn's disease, idiopathic thrombocytopenic purpura, rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus and chronic obstructive pulmonary disease (COPD). | View clinical data
triamcinolone
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including RA.
Clinical Use: Triamcinolone is used for its antiinflammatory or immunosuppressive actions in many conditions. For example, oral triamcinolone is used to treat conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, and breathing disorders. This drug is also used topically as an anti-inflammatory and anti-pruritic agent. Injectable forms of the drug may be used to reduce intra-articular joint pain, stiffness and swelling associated with rheumatoid and osteoarthritic arthritis, bursitis, epicondylitis, and tenosynovitis. | View clinical data
celecoxib
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Celecoxib is used to treat osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms. It is also used to reduce the number of colon and rectum polyps in patients with familial adenomatous polyposis. | View clinical data
rofecoxib
Immuno Disease Comments: Withdrawn from US market due to safety concerns.
Clinical Use: A non-steroidal anti-inflammatory drug previously used in the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, acture migraine and acute pain. Withdrawn from the US market in 2004 due to concerns about safety. | View clinical data
valdecoxib
Immuno Disease Comments: Withdrawn from US market due to safety concerns.
Clinical Use: Prior to manufacturer's withdrawl from the US and EU markets, valdecoxib was approved to treat osteoarthritis, rheumatoid arthritis and primary dysmennorhea. Reasons for withdrawl included increased cardiovascular risk (heart attack and stroke) and risk of a serious/fatal skin reaction. A prodrug of valdecoxib, , is approved for use in several countries other than the US. | View clinical data
etoricoxib
Immuno Disease Comments: Selective COX2 inhibitor approved for the treatment of many inflammatory conditions including RA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, chronic lower back pain, ankylosing spondylitis, acute pain and gout. There is no information regarding approval for medicinal use of etoricoxib on the US FDA website. Individual national agencies may have granted marketing approval. | View clinical data
flurbiprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Flurbiprofen is approved to treat the pain and inflammation associated with rheumatic diseases and other musculoskeletal disorders, as well as dysmenorrhoea, migraine and as postoperative analgesia. | View clinical data
ketoprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, primary dysmenorrhea and mild to moderate pain associated with musculotendinous trauma (sprains and strains), postoperative (including dental surgery) or postpartum pain. | View clinical data
methotrexate
Immuno Disease Comments: Approved drug for RA.
Clinical Use: Anti-tumour agent used in the treatment of acute lymphocytic leukemia (ALL), meningeal leukemia, non-Hogkin's lymphoma, breast, lung and head and neck cancers. Also indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole, and in the treatment of autoimmune conditions including severe psoriasis and rheumatoid arthritis. The first oral methotraxate solution (Xatmep®) was FDA approved in April 2017 for the treatment of ALL and polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients. A 2017 a paper reported that a combination of methotrexate with leflunomide relieves the immune defects and ameliorates symptoms of rheumatoid arthritis [139]. | View clinical data
fenoprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Fenoprofen is used to treat inflammatory conditions such as rheumatoid- and osteo-arthritis in addition to being used for pain relief. | View clinical data
IL-17A
Immuno Disease Comments: Approved therapy for RA.
BAFF
Immuno Disease Comments: BAFF is a drug target for RA.
naproxen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including RA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, and acute gout. Also used in pain relief in the treatment of primary dysmenorrhea. | View clinical data
sulindac
Immuno Disease Comments: Approved drug for RA.
Clinical Use: For acute relief or long term use in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder and acute gouty arthritis. | View clinical data
Bioactivity Comments: We have been unable to find affinity data for this drug to substantiate its MMOA | View biological activity
tofacitinib
Immuno Disease Comments: Approved drug for RA.
Clinical Use: Tofacitinib was intiailly approved for the treatment of rheumatoid arthritis. Marketed formulations contain tofacitinib citrate (PubChem CID 10174505).
In Feb 2016 Xelanj XR® was FDA approved as the first once-daily oral JAK inhibitor for rheumatoid arthritis.
In June 2018, FDA approval was expanded to include treatment of patients with moderate to severe ulcerative colitis (UC), subsequent to results from the Phase 3 OCTAVE studies, in which treatment of UC patients with tofacitinib met all primary endpoints and induced significant disase remission [87,93,105]. Xelanj XR® is not approved for UC.

A report in JCI Insight in September 2016 suggests that tofacitinib-induced immunosuppression can stimulate significant hair regrowth in patients with the autoimmune condition alopecia areata [23], although more extensive studies would need to be conducted before the drug could be approved for this indication. Click here to link to a list of tofacitinib/alopecia trials registered with ClinicalTrials.gov. | View clinical data
Bioactivity Comments: Like many first generation kinase inhibitors tofacitinib exhibits a high degree of broad kinome selectivity but is in reality a pan-JAK-inhibitor. Additional kinases inhibited by tofacitinib in biochemical and cellular assays are described in [90]. Tofacitinib is also reported to exhibit immunosuppressive activity which prevents organ rejection in mice and primates [15].
Despite clinical efficacy in ulcerative colitis, tofacitinib did not show significant efficacy as an induction and maintenance therapy over placebo, in Crohn's disease patients (as evaluated in Phase 2 studies NCT01393626 and NCT01393899) [92]. | View biological activity
IL-1 receptor antagonist
Immuno Disease Comments: A recombinant, non-glycosylated version of this protein is marketed as rheumatoid arthritis drug called Anakinra
IL-27
Immuno Disease Comments: Anti- and pro-inflammatory activities of IL-27 have been reported by a number of RA studies.
cipemastat
Immuno Disease Comments: An MMP1 clinical candidate which failed Phase 1 clinical trial in RA.
Clinical Use: This compound was being investigated as a treatment for rheumatoid arthritis [52] and as a tumor growth inhibitor [69]. It failed in Phase I clinical trials. | View clinical data
BMS-561392
Immuno Disease Comments: An investigational ADAM17 inhibitor with potential to reduce TNFα production in TNF-driven conditions such as RA.
Clinical Use: Potential treatment for overproduction of TNF alpha, such as rheumatoid arthritis (phase 2 trial) or inflammatory bowel disease [47]. Hoerver since this report there appears to have been no further development of this compound. | View clinical data
certolizumab pegol
Immuno Disease Comments: An anti-TNFα therapy approved for RA.
Clinical Use: Used to treat rheumatoid arthritis (RA) and Crohn's disease [18]. May also have some effect in related conditions such as axial spondyloarthritis [110]. The EMA granted Europe-wide approval for the use of this drug in patients with RA (moderate to severe, active disease and severe, active and progressive disease), axial spondyloarthritis and psoriatic arthritis in 2009. FDA approval was expanded to include treatment of moderate-to-severe plaque psoriasis, in June 2018. | View clinical data
Bioactivity Comments: Certolizumab pegol neutralises soluble TNFα in vitro, with an IC90 of 3ng/ml [88], neutralises the effects mediated by membrane bound TNFα, and inhibits production of IL-1β in monocytes stimulated with LPS. | View biological activity
golimumab
Immuno Disease Comments: An anti-TNFα therapy approved for RA.
Clinical Use: Used in adults with various inflammatory conditions [140] e.g. moderate to severe active rheumatoid arthritis [59], active psoriatic arthritis, active ankylosing spondylitis and moderate to severe ulcerative colitis. | View clinical data
rituximab
Immuno Disease Comments: An anti-CD20 therapy approved for RA.
Clinical Use: Used to treat CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Rituximab is also used to suppress antibody-mediated rejection in living-donor kidney recipients prior to an ABO-incompatible transplant [35,76]. A modified formulation containing rituximab + human hyaluronidase (Rituxan Hycela) that can be delivered subcutaneously (the original rituximab only formulation was administered intravenously) was FDA approved in June 2017 for the treatment of previously untreated and relapsed or refractory follicular lymphoma, previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL). In June 2018, the FDA approved the use of rituximab as a much needed treatment for the potentially life-threatening skin disease pemphigus vulgaris that can be used for adults patients with moderate to severe disease. | View clinical data
Bioactivity Comments: The patents covering rituximab do not contain any data regarding antibody-antigen affinity [2-3], but a dissociation constant is provided by Stein et al (2004) [111]. | View biological activity
leflunomide
Immuno Disease Comments: A DMARD approved for active RA.
Clinical Use: Used to treat active rheumatoid arthritis (improve physical function and slow progression), prevention of acute/chronic rejection following organ transplant (as an FDA designated orphan drug). | View clinical data
abatacept
Immuno Disease Comments: Approved drug for RA.
Clinical Use: Used to treat moderate to severe rheumatoid arthritis and juvenile rheumatoid arthritis. In July 2017, FDA approval was extended to include treatment of active psoriatic arthritis.
A Phase II clinical trial (NCT00505375) has been completed, evaluating the ability of abatacept to stop autoimmune destruction of any remaining active β cells in patients recently diagnosed with type 1 diabetes mellitus- see [72] for an explanation of the rationale behind this therapeutic approach, and [25] which points to some of its drawbacks. | View clinical data
Bioactivity Comments: In a cell based CD80/86 inhibition assay abatacept inhibits IL-2 release with an IC50 of 22.6 nM [29]. | View biological activity
anakinra
Immuno Disease Comments: An IL-1RA mimetic approved to treat RA that is resistant to other anti-rheumatic drugs.
Clinical Use: Anakinra is used to treat the symptoms of moderate to severe rheumatoid arthritis and may also help slow the progress of the disease. This drug is usually tried after treatment with other arthritis medications has been unsuccessful. | View clinical data
tocilizumab
Immuno Disease Comments: Tocilizumab was the first humanized mAb to be developed against the human the IL-6 receptor, and is now an approved therapeutic for RA.
Clinical Use: Approved as a treatment for rheumatoid arthritis and systemic and polyarticular juvenile idiopathic arthritis.
In May 2017 tocilizumab became the first FDA approved drug for the treatment of adults with giant cell arteritis.
Phase 3 clinical trials for immune conditions including ankylosing spondylitis, hand osteoarthritis, systemic sclerosis and primary Sjögren's syndrome (pSS) are ongoing. Tocilizumab was initally used off-label to manage severe or life-threatening cytokine release syndrome (CRS), which is a serious, and potentially life-threatening side effect of CAR T-cell therapy. In September 2017, the FDA extended tocilizumab approval to include treatment of CAR T-cell therapy-induced CRS. It was approved particularly to manage CRS in patients ≥2 years of age receiving tisagenlecleucel (Kymriah®,CTL019), the first CAR T-cell therapy approved for relapsed and refractory B-cell ALL. | View clinical data
Bioactivity Comments: Unfortunately, we have been unable to find publicly available data providing a binding affinity for this antibody at its molecular target. | View biological activity
pateclizumab 60
Immuno Disease Comments: Pateclizumab failed to show clinical efficacy in patients with active RA after 12 weeks of treatment.
Clinical Use: Pateclizumab (as research code MLTA3698A) has completed Phase 2 clinical trial in patients with active rheumatoid arthritis. In this trial (NCT01225393) MLTA3698A plus a DMARD was directly compared with plus a DMARD, and results were reported by Kennedy et al. (2014) [60]. | View clinical data
Bioactivity Comments: Safety, pharmacokinetics, and biologic activity of pateclizumab are reported in Emu et al. (2012) [34]. | View biological activity
prednisone
Immuno Disease Comments: Approved drug for RA.
Clinical Use: Used to treat a wide variety of inflammatory conditions. | View clinical data
azathioprine
Immuno Disease Comments: Approved drug for RA.
Clinical Use: Used to reduce organ rejection in transplant patients and to treat autoimmune diseases such as rheumatoid arthritis, Crohn's disease, lupus erythematosus and ulcerative colitis. | View clinical data
Bioactivity Comments: Azathioprine is reported to inhibit peptidylarginine deiminase 4 (PADI4), albeit with very low in vitro affinity [64]. PADI enzymes catalyze the hydrolytic deimination of protein arginine to produce protein citrulline and ammonia [58] and cause chromatin decondensation. Dysregulated PADI4 activity may be involved in cancer progression as it is overexpressed in many malignant tumours, where enhanced chromatin decondensation is involved in promoting pluripotency and stem cell maintenance. | View biological activity
diflunisal
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Dislusinal is used to treat moderate pain, and responsive inflammatory conditions including osteo- and rheumatoid arthritis. | View clinical data
Bioactivity Comments: We have been unable to find affinity data for this drug to substantiate its MMOA and have therefore not tagged a primary drug target. | View biological activity
etodolac
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA and OA.
Clinical Use: Etodolac is indicated for acute or long-term use in osteo- and rheumatoid arthritis. | View clinical data
meclofenamic acid
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used to treat muscular pain, arthritis and dysmenorrhea. There is no information regarding approval for clinical use of this drug on the US FDA website. Other national approval agencies may have granted marketing authorisation. | View clinical data
meloxicam
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: This drug is used to treat pain and inflammation associated with osteo- and rheumatoid arthritis. | View clinical data
nabumetone
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used to treat pain and inflammation associated with osteo- and rheumatoid arthritis. | View clinical data
Bioactivity Comments: We have been unable to find publicly available affinity data for this drug to substantiate its MMOA, and have therefore not tagged a primary drug target. | View biological activity
oxaprozin
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used to treat pain or inflammation caused by osteo- and rheumatoid arthritis. | View clinical data
penicillamine
Immuno Disease Comments: An immunosuppressant used to manage RA.
Clinical Use: As a chelating agent penacillamine is used to remove copper from tissues (in patients whose copper-transporting ATPase, ATP7B, is non-functional causing Wilson's disease), to treat cystinuria, and to treat lead poisoning. As an immunosuppressant, this drug is used to treat rheumatoid arthritis and chronic active hepatitis. | View clinical data
Bioactivity Comments: As the molecular target(s) of this drug are not definitively described, we have not tagged a primary drug target. | View biological activity
piroxicam
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used to treat rheumatoid and osteoarthritis, primary dysmenorrhoea and postoperative pain. | View clinical data
suprofen
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used as an antiarthritic and to treat inflammations of the eye. Marketing authorisation has been discontinued in the US, but other national approval agencies may continue to grant marketing authorisation. | View clinical data
tolmetin
Immuno Disease Comments: NSAID used to treat the pain and inflammation of RA.
Clinical Use: Used to relieve the symptoms of osteo- and rheumatoid arthritis. | View clinical data
Bioactivity Comments: We have been unable to find publicly available affinity data for this drug to substantiate its MMOA and have therefore not tagged a primary drug target. | View biological activity
AZD5672
Immuno Disease Comments: Failed clinical candidate for RA (showed no significantl efficacy).
Clinical Use: AZD5672 was tested as a potential treatment for rheumatoid arthritis, however, the compound failed to show efficacy in clinical trial, and development was ceased. | View clinical data
AZ11657312 (salt free)
Immuno Disease Comments: Experimental compound.
Bioactivity Comments: Note that bioactivity will be associated with the hydrochloride salt. Pending publication, the data presented here is derived from the compound's record in AstaZeneca's Open Innovation Pharmacology Toolbox | View biological activity
mavrilimumab
Immuno Disease Comments: Clinical candidate therapeutic for RA (Phase 2 studies completed).
Clinical Use: A phase II clinical trial (NCT01712399) of mavrilimumab in adult rheumatoid arthritis patients has been completed (May 2017). | View clinical data
Bioactivity Comments: Results presented in patent US8263075 [21] show that mavrilimumab (antibody 6) has potent effects in biological assays, including inhibition of GM-CSF-induced proliferation of TF-1 ( human erythroleukemic) cells and activity in GM-CSF-induced shape change assays using human granulocytes. | View biological activity
dilmapimod
Immuno Disease Comments: Phase 2 candidate for RA, but has not progressed further.
Clinical Use: SB-681323 has been assessed to Phase II in clinical trial for indications including chronic obstructive pulmonary disease, rheumatoid arthritis and neuropathic pain, although there are no currently active trials (as of Nov 2014). Click here to view the list of completed SB-681323 trials at ClinicalTrials.gov. | View clinical data
talmapimod
Immuno Disease Comments: Phase 2 candidate for RA, but has not progressed further.
Clinical Use: Talmapimod has been assessed in several completed Phase II clinical trials for myelodysplastic syndromes and active rheumatoid arthritis. Click here for ClinicalTrials.org's full list of completed talmapimod (SCIO-469) trials. There are no active trials registered with ClinicalTrials.org (Nov 2014). | View clinical data
AZD9056
Immuno Disease Comments: Reached Phase 2 clinical evaluation in RA, but development was discontinued.
Clinical Use: AZD9056 was developed for the treatment of inflammatory conditions such as rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD) and Crohn’s disease. Phase II trial NCT00520572 for RA has been completed. There are no active trials in progress (Nov 2014). | View clinical data
Bioactivity Comments: The NIH National Center for Advancing Translational Sciences (NCATS) record for AZD9056 provides bioactivity data as follows: The IC50 for AZD9056-induced inhibition of pro-inflammatory IL-1β and IL-18 release from human peripheral monocytes is 10-13nM. | View biological activity
spebrutinib
Immuno Disease Comments: Completed Phase 2 clinical evaluation in RA (see NCT01975610).
Clinical Use: Spebrutinib has been granted orphan drug designation by the EMA (using the chemical name n-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide benzenesulfonic acid salt) for the treatment of B-cell chronic lymphocytic leukemia (CLL). Spebrutinib (as research code CC-292) has been compared with placebo as a co-therapy with for active rheumatoid arthritis, in completed clinical trial NCT01975610. In addition it is in various Phase I trials for B-cell lymphomas. Click here to view these trials at ClinicalTrials.gov. | View clinical data
BMS-582949
Immuno Disease Comments: Reached Phase 2 clinical evaluation in RA and plaque psoriasis, but development has not progressed.
Clinical Use: BMS-582949 was assessed in Phase II clinical trials for atherosclerosis (NCT00570752) and rheumatoid arthritis (NCT00605735). There are no currently active trials for this compound (Nov 2014). | View clinical data
sirukumab
Immuno Disease Comments: Phase 3 clinical candidate for RA (see NCT01856309).
Clinical Use: Phase 3 clinical trials assessing sirukumab for RA have been completed or are still ongoing (Oct 2017). Click here to link to ClinicalTrials.gov's listing of Phase 3 sirukumab trials. Other trials are collecting data in additional inflammatory conditions including lupus nephritis [101], cutaneous lupus erythematosus, systemic lupus erythematosus and giant cell arteritis.
Research is beginning to indicate that the disease pathophysiology of depression may have an immune component [30,53,86], and reviewed in [137]. In particular, IL-6 has been identified as a susceptibility gene for major depressive disorder (MDD), with the promoter polymorphism rs1800797 showing a marginally significant correlation with cortical IL-6 expression [138]. This and other work (including [86]) has led to clinical trial of sirukumab as an adjunct to conventional antidepressant therapy in patients with MDD (see Phase 3 trial NCT02473289). | View clinical data
tabalumab
Immuno Disease Comments: Tabalumab was a clinical candidate therapeutic for RA.
Clinical Use: Click here to link to a list of the Phase 3 tabalumab trials registered with ClinicalTrials.gov.. Efficacy and safety of tabalumab in SLE patients is reported in [116], results which indicate an improved response rate and a reduced frequency of flares in the treatment group receiving 120 mg every 2 weeks relative to placebo. | View clinical data
Bioactivity Comments: In patent US7317089 a KD for the interaction between antibody 4A5-3.1.1-B4 and human TNFSF13B is reported as 38µM [61]. However, this appears to be a very low affinity, considering the patent abstract suggests a requirement for the KD to be <10nM. We have therefore entered the 10nM figure in the interaction table below. | View biological activity
secukinumab
Immuno Disease Comments: Phase 3 study in RA was terminated (see NCT01770379).
Clinical Use: Secukinumab is approved by the US FDA for the treatment of plaque psoriasis.
Secukinumab also met its clinical endpoints in Phase III clinical trial for ankylosing spondylitis (NCT01649375) [6], and was FDA approved for this indication and psoriatic arthritis [80,83] in January 2016.
The antibody is also in Phase II clinical trial for multiple sclerosis (NCT01874340) based on results from experiments in an animal model of the disease (experimental autoimmune encephalomyelitis, EAE) and in vitro human cell assays [33]. | View clinical data
decernotinib
Immuno Disease Comments: Developed as a potential treatment for RA, but no evidence of progress in clinical development.
Clinical Use: Decernotinib reached Phase III clinical trial as a potential treatment for rheumatoid arthritis (RA), but development appears to have been terminated, apparently for strategic reasons. | View clinical data
peficitinib
Immuno Disease Comments: Phase 3 clinical candidate for RA.
Clinical Use: Peficitinib is being assessed in Phase III clinical trial as a potential treatment for rheumatoid arthritis (RA). A Phase IIa trial in patients with moderate to severe psoriasis has produced encouraging results [95]. | View clinical data
Bioactivity Comments: Note that some bioactivity data may be generated using peficitinib hydrobromide (PubChem CID 67998300). We have tagged JAK3 as the primary molecular target for this compound for data metric purposes only, and fully acknowledge its pan-JAK activity. | View biological activity
vobarilizumab
Immuno Disease Comments: Phase 2 clinical candidate for RA (see NCT02518620).
Clinical Use: Vobarilizumab (as research code ALX-0061) has reached Phase II clinical trial. See NCT02437890 (SLE) and NCT02518620 (RA) as examples. | View clinical data
Bioactivity Comments: Binding affinity (KD) for human serum albumin is 22nM [120]. | View biological activity
itacitinib
Immuno Disease Comments: Phase 2 study NCT01626573 in RA has been completed.
Clinical Use: INCB039110 is being assessed in Phase II clinical trial as a potential treatment for indications such as rheumatoid arthritis (RA), post essential thrombocythemia myelofibrosis, chronic plaque psoriasis and non-small cell lung cancer (NSCLC). | View clinical data
amelubant
Immuno Disease Comments: No progress in development beyond Phase 2 trial in RA.
Clinical Use: Amelubant (BIIL 284) reached Phase 2 clinical trial for inflammatory conditions including chronic obstructive pulmonary disease (COPD), bronchial asthma and rheumatoid arthritis (RA). | View clinical data
Bioactivity Comments: As a prodrug, amebulant has very little affinity for the BLT1 receptor [9]. Bioactivity is attributed to its active metabolite, . | View biological activity
SC-67655
Immuno Disease Comments: Experimental compound with predicted application in RA.
lenzilumab
Immuno Disease Comments: Clinical candidate for RA (maximum Phase 2).
Clinical Use: Lenzilumab has completed Phase II clinical trial for uncontrolled asthma, whereas a Phase II study in patients with inadequately controlled rheumatoid arthritis has been terminated. A Phase I trial in patients with previously treated chronic myelomonocytic leukemia (CMML) is ongoing [91]. | View clinical data
deflazacort
Immuno Disease Comments: Approved corticosteroid that can be prescribed for RA.
Clinical Use: Deflazacort can be prescribed for many inflammatory conditions including asthma, rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis, idiopathic thrombocytopenic purpura, polymyalgia rheumatica, systemic lupus erythematosus and ulcerative colitis. More recently approved to treat Duchenne muscular dystrophy [46]. | View clinical data
Bioactivity Comments: In vitro binding to rat kidney, thymus and liver glucocorticoid receptors is reported in [73]. | View biological activity
VRT-043198
Immuno Disease Comments: Experimental compound with predicted application in inflammatory skin conditions and RA.
Bioactivity Comments: Inhibits caspase-1 (Ki = 0.8 nM) and caspase-4 (Ki < 0.6 nM) and shows 100- to 10,000-fold selectivity against caspases -3 and -6 to -9. Inhibits the release of interleukin (IL)-1β and IL-18, but has little effect on the release of several other cytokines, including IL-1α, tumor necrosis factor-α, IL-6 and IL-8 [128]. | View biological activity
eldelumab
Immuno Disease Comments: No progress beyond Phase 2 trial.
Clinical Use: Eldelumab has been evaluated in Phase II clinical trials for rheumatoid arthritis [136] and ulcerative colitis (NCT00656890) [79]. The antibody showed efficacy in both conditions. | View clinical data
Bioactivity Comments: Eldelumab does not bind other identified CXCR3 ligands (a.k.a. MIG) and (a.k.a. ITAC) [27]. | View biological activity
MK-0812
Immuno Disease Comments: Phase 2 trial NCT00542022 in RA was completed- no further progress recorded.
Clinical Use: MK-0812 has completed a Phase II efficacy, tolerability and safety clinical trial in patients with rheumatoid arthritis (NCT00542022), and a Phase II trial in patients with relapsing-remitting multiple sclerosis (NCT00239655). | View clinical data
Bioactivity Comments: MK-0812 blocks all MCP-1-driven CCR2 activation in vitro and inhibits migration of rhesus monkey monocytes to the skin in an experimental hypersensitivity reaction in vivo [132]. | View biological activity
MRL-367
Immuno Disease Comments: Experimental compound with predicted application in RA.
Bioactivity Comments: In a RORγ/Gal4 cell-based reporter assay MRL-367 inhibits RORγt with an IC50 of 41nM, and shows no significant activity against a panel of related nuclear hormone receptors [26]. | View biological activity
MRL-248
Immuno Disease Comments: Experimental compound with predicted application in RA.
Bioactivity Comments: In a RORγ/Gal4 cell-based reporter assay MRL-248 inhibits RORγt with an IC50 of 118nM, and shows no significant activity against a panel of related nuclear hormone receptors [26]. | View biological activity
timolumab
Immuno Disease Comments: Completed Phase 1 clinical trial NCT00851240.
Clinical Use: Timolumab (with research code BTT1023) is being evaluated in Phase II clinical trial NCT02239211, for its potential to treat patients with primary sclerosing cholangitis, an uncommon and progressive disease of the bile ducts characterised by inflammation and obliterative fibrosis. Phase I studies for RA and psoriasis have been completed (2010/11). | View clinical data
PLX5622
Immuno Disease Comments: Phase 1b clinical trial completed (see NCT01329991).
Clinical Use: A Phase 1b study of PLX5622 in RA patients receiving therapy has been completed- see NCT01329991. | View clinical data
Bioactivity Comments: In preclinical studies, PLX5622 has demonstrated significant disease suppression in arthritis models. | View biological activity
cabiralizumab
Immuno Disease Comments: Phase 1 in RA terminated and development discontinued.
Clinical Use: Cabiralizumab (research code FPA008) is in early stage clinical trials for solid tumours and rheumatoid arthritis (RA). Click here to link to all FPA008 trials registered with ClinicalTrials.gov. Immuno-oncology trials are evaluating cabiralizumab monotherapy and combination with the immune checkpoint inhibitor , anti-PD-1 mAb., in selected advanced solid tumours (Phase 1). | View clinical data
GSK583
Immuno Disease Comments: Experimental compound with predicted application in RA.
Bioactivity Comments: A kinome scan shows that at 1µM GSK583 is selective for RIP2 kinase in the panel of 300 kinases tested [49]. GSK583 is effective in cellular asays assessing its ability to inhibit pro-inflammatory cytokine release in response to NOD2 pathway actvation by muramyldipeptide (MDP). | View biological activity
clazakizumab
Immuno Disease Comments: No progress beyond Phase 2 trial.
Clinical Use: Phase 2 clinical trials in patients with active rheumatoid arthritis (NCT01373151, results reported in [129]), psoriatic arthritis (NCT01490450, results in [82]), cachexia resulting from non-small cell lung cancer [7,74], acute graft versus host disease (GvHD) and oral mucositis caused by head and neck cancer have been completed. Click here to link to ClinicalTrials.gov's list of clazakizumab (ALD518 and BMS-945429) trials. | View clinical data
briakinumab
Immuno Disease Comments: Clinical development for RA has been terminated.
Clinical Use: Results from a Phase 2 clinical trial (NCT00292396) evaluating briakinumab in patients with moderate to severe chronic plaque psoriasis are reported in [63]. Several Phase 3 trials comparing briakinumab against placebo, and (two approved anti-psoriatic drugs) for moderate to severe chronic plaque psoriasis (link here to a list of these trials on ClinicalTrials.gov) have been completed. Clinical development of briakinumab for rheumatoid arthritis, Crohn's disease and multiple sclerosis has been terminated. As of May 2017, there are no active clinical trials evaluating this antibody. | View clinical data
upadacitinib
Immuno Disease Comments: Phase 3 clinical candidate for RA.
Clinical Use: ABT-494 has reached Phase 3 clinical trial for rheumatoid arthritis (RA). Evaluation of upadacitinib's potential in additional immune-mediated conditions (psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and atopic dermatitis) are ongoing. Click here to link to ClinicalTrials.gov's list of Phase 3 ABT-494 trilas. | View clinical data
Bioactivity Comments: In a kinase screening panel, only two other kinases, Rock1 and Rock2 have IC50s below 1000nM [127]. | View biological activity
fezakinumab
Immuno Disease Comments: Completed Phase 2 trial for RA (see NCT00883896).
Clinical Use: Fezakinumab (ILV-094) has reached Phase 2 for atopic dermatitis (NCT01941537 ongoing), rheumatoid arthritis (NCT00883896 completed) and Phase 1 for psoriasis (NCT00563524 completed). | View clinical data
Bioactivity Comments: Fezakinumab shows cross-species reactivity, blocking IL-22 receptor activation and cellular proliferation induced by murine, monkey and rat IL-22 in addition to the human cytokine [38]. | View biological activity
TG6-129
Immuno Disease Comments: Probe compound for experimental use.
fenebrutinib
Immuno Disease Comments: Phase 2 clinical candidate for RA (see NCT02983227 and NCT02833350).
Clinical Use: GDC-0853 has reached Phase 2 clinical trial in patients with rheumatoid arthritis (RA: see NCT02833350), and Phase 1 in patients with resistant B-cell lymphoma or chronic lymphocytic leukemia (CLL). | View clinical data
TAK-715
Immuno Disease Comments: An experimental TNFα-reducing compound, developed for anti-inflammatory activity.
Bioactivity Comments: TAK-715 inhibits LPS-induced TNFα production in vitro and in vivo, shows good bioavailability in rodents and no inhibitory activity for major CYP450 drug-metabolising enzymes [84]. It shows efficacy in a rat adjuvant-induced arthritis model. | View biological activity
BMS-817399
Immuno Disease Comments: BMS-817399 was a clinical candidate for RA that reached Phase 2 clinical trial
Clinical Use: BMS-817399 failed to show clinical efficacy in a 12 week Phase 2 proof-of-concept trial in patients with moderate to severe RA. | View clinical data
CHMFL-BTK-11
Immuno Disease Comments: A pharmacological tool suitable for investigating BTK mediated signaling in RA.
atacicept
Immuno Disease Comments: Atacicept is in clinical development for the treatment of RA.
Clinical Use: Atacicept is at various stages of clinical development for different autoimmune conditions- e.g. Phase 2/3 for SLE [43] and Phase 2 for rheumatoid arthritis [122] and optic neuritis (a demyelinating inflammation of the optic nerve) [108]. | View clinical data
Bioactivity Comments: WO2002094852 provides binding data for BAFF but not for APRIL, ZNTF4 and ZNTF2 respectively in this patent [99]. | View biological activity
GSK2982772
Immuno Disease Comments: Clinical candidate in RA.
Clinical Use: GSK2982772 is in Phase 2 clinical trials in psoriasis (NCT02776033), rheumatoid arthritis (NCT02858492), and ulcerative colitis (NCT02903966). | View clinical data
Bioactivity Comments: In a screening panel 10μM GSK2982772 did not inhibit any of the 339 kinases tested by >50% (a level assessed as being inactive). GSK2982772 prevented TNF-induced necrotic cell death, and was effective in an ulcerative colitis explant assay for blocking spontaneous cytokine release [50]. | View biological activity
PF-06651600
Immuno Disease Comments: Phase 1 clinical candidate for RA (NCT02969044).
Clinical Use: PF-06651600 has completed Phase 1clinical trial for inflammatory bowel disease (see NCT02309827). Phase 1 studies in rheumatoid arthritis, ulcerative colitis and alopecia areata are underway. | View clinical data
Bioactivity Comments: PF-06651600 exhibits favourable selectivity against a screening panel of 305 kinases in vitro, and shows measurable inhibition of 7 of the 10 other kinases which share a cysteine residue analogous to Cys-909 in the JAK3 ATP binding site (these were BMX, ITK, TXK, TEC, BTK, BLK and HER4) [118].
ATP concentration for JAK3 is 4 μM at Km and for JAK1 is 40 μM at Km, but some assays reported in [118] were carried out at 1 mM ATP . | View biological activity
PFK15 141
Immuno Disease Comments: Postulated to inhibit fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis.
CP-195543
Immuno Disease Comments: CP-195543 was a Phase 2 clinical candidate for RA (see NCT00424294). Development was discontinued due to its poor tolerability profile and high discontinuation rate.
Clinical Use: Phase 2 clinical trial NCT00424294 which was designed to evaluate the efficacy, safety and tolerability of CP-195543 and dual therapy in rheumatoid arthritis patients was terminated in 2007 following interim efficacy and safety analysis, which showed that CP-195543 exhibited a poor tolerability profile and high discontinuation rate. | View clinical data
rabeximod
Immuno Disease Comments: Phase 2 evaluation as an adjunct to methotrexate therapy in RA has been completed- see NCT00525213
Clinical Use: Phase 2 clinical trial NCT00525213 that was evaluating rabeximod (Rob 803) in patients with moderate or severe active rheumatoid arthritis has been completed, but results have not been published in peer reviewed literature. | View clinical data
BMS-986142
Immuno Disease Comments: Phase 2 clinical candidate for RA- see NCT02638948.
Clinical Use: Efficacy of BMS-986142 will be evaluated in rheumatoid arthritis patients in Phase 2 clinical study NCT02638948. A Phase 2 proof of concept study in Sjögren's syndrome (NCT02843659) was terminated early due to an inability to meet protocol objectives. | View clinical data
tregalizumab 121
Immuno Disease Comments: Tregalizumab failed to show clinical efficacy in Phase 2 trial (NCT01999192), and development was discontinued.
Clinical Use: Phase 2 clinical trial (NCT01999192) in patients with active RA and an inadequate response to , was terminated early as the therapy failed to show clinical efficacy above methotrexate control [121]. | View clinical data
Bioactivity Comments: Patent WO2004083247 A1 which claims tregalizumab, does not provide any affinity values for tregalizumab-CD4 binding, but does contain experimental evidence of the antibody's in vitro and in vivo biological effects [131]. | View biological activity
BMS-986195
Immuno Disease Comments: Phase 1 candidate for RA- all studies completed to date (March 2018) have been conducted in healthy subjects, NOT in RA patients (e.g. NCT03131973 and NCT02705989).
Clinical Use: BMS-986195 has completed Phase 1 trials in healthy subjects and has not yet been evaluated in patients with RA (March 2018). | View clinical data
pelubiprofen 16
Immuno Disease Comments: Results from a Phase 3 clinical trial that compared 6 weeks treatment with pelubiprofen to celecoxib treatment, indicate that this novel drug is as effecive as the comparator. However, patients given pelubiprofen suffered more gastrointestinal adverse effects than did the celecoxib cohort.
Clinical Use: Pelubiprofen has completed Phase 3 clinical evaluations for the management of the inflammation and pain associated with rheumatoid arthritis (NCT01781702) and chronic back pain (NCT02375633). | View clinical data
Bioactivity Comments: Pelubiprofen showed potent analgesic, antiadjuvant arthritis activities, and antipyretic properties in in vivo models [117]. We have been unable to find an inhibitory constant for pelubiprofen's inhibition of the COX enzymes in peer reviewed literature. It's mechanism of action has been defined by biological assays and pharmacological effects in in vivo [4,16,65,117]. | View biological activity
andecaliximab
Immuno Disease Comments: Phase 2 clinical trial in RA patients has been terminated (see NCT02862574).
Clinical Use: Andecaliximab (GS-5745) is being evaluated in various clinical trials (max Phase 3) for cancers and inflammatory conditions. Click here to link to all of the trials registered with ClinicalTrials.gov. Trials in ulcerative colitis and Crohn's disease were terminated early (2016) due to meeting pre-specified futility and efficacy criteria in an interim analysis of unblinded efficacy and safety data. A Phase 2 study in rheumatoid arthritis has also been terminated. Evaluation for anti-cancer efficacy appears to be ongoing. Phase 2 trial NCT02864381 is evaluating andecaliximab in combination with the anti-PD-1 checkpoint inhibitor in unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma. | View clinical data
fostamatinib 67
Immuno Disease Comments: Phase 3 clinical candidate for RA.
Clinical Use: Fostamatinib (as the disodium hexahydrate salt) received FDA approval for the treatment of chronic immune thrombocytopenia (ITP) [89] in April 2018, in particular for the treatment of patients with an inadequete response to previous treatment.
Fostamatinib has completed Phase 3 clinical trials for rheumatoid arthritis [77] (NCT01197534 & NCT01197755), and Phase 2 for a range of solid tumours (NCT00923481). | View clinical data
Bioactivity Comments: As fostamatinib is a prodrug it is unlikely to have intrinsic inhibitory activity. Bioactivity will be associated with its active form, tamatinib. | View biological activity
pamapimod 1
Immuno Disease Comments: Phase 2 clinical studies evaluating pamapimod (RO4402257) in RA patients either as a monotherapy (NCT00303563), or as an adjunct to methotrexate therapy (NCT00316771) have been completed. As a monotherapy pamapimod was not as effective as methotrexate, and in patients on a stable methotrexate regimen pamapimod showed no significant improvement in efficacy outcomes compared to placebo.
Clinical Use: Pamapimod reached Phase 2 clinical evaluation as an immunomodulator for rheumatoid arthritis, but development was terminated due to a lack of clinical efficacy, either as a monotherapy, or as an adjunct to methotrexate [1,22]. | View clinical data
Bioactivity Comments: Pamapimod exhibits submicromolar binding affinity for only seven out of >300 kinases tested [42]. It binds p38α (MAPK14) and p38β (MAPK11), but not p38γ (MAPK12) or p38δ (MAPK13). Pamapimod potently inhibited cytokine production in a selection of in vitro and in vivo models, including inhibition of TNFα production by human monocytic THP-1 cells, and inhibition of LPS-induced IL-1β production in human whole blood. | View biological activity

References

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