Inflammatory bowel disease 1; IBD1

Disease ID:1028
Name:Inflammatory bowel disease 1; IBD1
Associated with:1 target
8 immuno-relevant ligands
Synonyms
Inflammatory bowel disease
Database Links
Disease Ontology: DOID:0050589
OMIM: 266600

Targets

NLRP3

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
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 [3]. Hoerver since this report there appears to have been no further development of this compound. | View clinical data
3beta-Hydroxy-20(29)-lupene
Immuno Disease Comments: Experimental compound with predicted application in inflammatory bowel diseases.
Bioactivity Comments: No direct binding targets were identified but the authors propose that Lupeol acts through a specific receptor and down-stream signaling pathways, such as p38 MAPK, inhibits IRF5 and possibly other transcription factors critical for M1 polarization, resulting in decreased expression of M1 genes and enhanced expression of M2 genes, thereby causing an M1 to M2 switch [7]. | View biological activity
MRL-367
Immuno Disease Comments: Experimental compound with predicted application in inflammatory bowel disease.
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 [2]. | View biological activity
MRL-248
Immuno Disease Comments: Experimental compound with predicted application in inflammatory bowel disease.
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 [2]. | View biological activity
GSK583
Immuno Disease Comments: Experimental compound with predicted application in inflammatory bowel disease.
Bioactivity Comments: A kinome scan shows that at 1µM GSK583 is selective for RIP2 kinase in the panel of 300 kinases tested [4]. 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
bihelical apoA-I mimetic peptide 5A
Immuno Disease Comments: Experimental compound with predicted application in inflammatory bowel disease.
Bioactivity Comments: In vitro, the 5A peptide was able to solubilize phospholipid vesicles and stimulated cholesterol and phospholipid efflux by the ABCA1 transporter with high specificity but no affinity data has yet been reported [5]. | View biological activity
etrasimod
Immuno Disease Comments: Phase 2 clinical candidate for IBD patients (including UC and Crohn's disease) with active skin manifestations (see proof of concept study NCT03139032).
Clinical Use: Etrasimod (APD334) is in Phase 2 extension study clinical trial in patients with moderately to severely active ulcerative colitis (see NCT02536404). | View clinical data
Bioactivity Comments: In in vitro β-arrestin recruitment assays APD334 has no measurable activity at S1P2 and S1P3 receptors, and low activity at S1P4 receptors [1]. EC50 for S1P5 receptors is around 4-fold lower than for the primary target S1P1. APD334 has similar ability to induce cAMP accumulation across S1P1 receptors from species including human, rat, mouse, monkey and dog. APD334 produces robust lymphocyte lowering in several preclinical species, and is effective in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis [1]. | View biological activity
PF-06651600
Immuno Disease Comments: Phase 1 clinical candidate for IBD (NCT02309827).
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) [6].
ATP concentration for JAK3 is 4 μM at Km and for JAK1 is 40 μM at Km, but some assays reported in [6] were carried out at 1 mM ATP . | View biological activity

References

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1. Buzard DJ, Kim SH, Lopez L, Kawasaki A, Zhu X, Moody J, Thoresen L, Calderon I, Ullman B, Han S et al.. (2014) Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. ACS Med Chem Lett, 5 (12): 1313-7. [PMID:25516790]

2. de Wit J, Al-Mossawi MH, Hühn MH, Arancibia-Cárcamo CV, Doig K, Kendrick B, Gundle R, Taylor P, Mcclanahan T, Murphy E et al.. (2016) RORγt inhibitors suppress TH17 responses in inflammatory arthritis and inflammatory bowel disease. J. Allergy Clin. Immunol., 137 (3): 960-3. [PMID:26611672]

3. Grootveld M, McDermott MF. (2003) BMS-561392. Bristol-Myers Squibb. Curr Opin Investig Drugs, 4 (5): 598-602. [PMID:12833656]

4. Haile PA, Votta BJ, Marquis RW, Bury MJ, Mehlmann JF, Singhaus Jr R, Charnley AK, Lakdawala AS, Convery MA, Lipshutz DB et al.. (2016) The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. J. Med. Chem., 59 (10): 4867-80. [PMID:27109867]

5. Tabet F, Remaley AT, Segaliny AI, Millet J, Yan L, Nakhla S, Barter PJ, Rye KA, Lambert G. (2010) The 5A apolipoprotein A-I mimetic peptide displays antiinflammatory and antioxidant properties in vivo and in vitro. Arterioscler. Thromb. Vasc. Biol., 30 (2): 246-52. [PMID:19965776]

6. Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R et al.. (2017) Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J. Med. Chem., 60 (5): 1971-1993. [PMID:28139931]

7. Zhu Y, Li X, Chen J, Chen T, Shi Z, Lei M, Zhang Y, Bai P, Li Y, Fei X. (2016) The pentacyclic triterpene Lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease. Int. Immunopharmacol., 30: 74-84. [PMID:26655877]