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Synonyms: adavivint (deprecated INN) | SM0-4690 | SM04690
Compound class:
Synthetic organic
Comment: Lorecivivint (SM04690, formerly adavivint) is a Wnt pathway inhibitor being developed by Samumed for immunomodulatory potential. It acts downstream of β-catenin, and its molecular targets are the intranuclear kinases CLK2 and DYRK1A through which it inhibits phosphorylation of serine/arginine-rich splicing factors, and SIRT1 and FOXO1 respectively [3]. Wnt signalling is upregulated in tissues from osteoarthritic joints, and drives disease pathologies including inflammation [5]. Wnt pathway inhibition by lorecivivint is being investigated as a disease-modifying treatment for osteoarthritis.
SM04690 is example 10 as claimed in patent US20160297812 [4]. The chemical structure shown here was produced using the IUPAC name submitted to the WHO for the INN adavivint (via SMILES generated using Chemicalize) which was later renamed as lorecivivint. This SMILES string resolves to PubChem CID 123710737, although some of the double bonds in the molecule are not fully resolved, when compared to the images in US20160297812. CID 89837869 is an alternative representation. 
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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Summary of Clinical Use  |
| SM04690 is being evaluated in Phase 2 clinical trial as a novel disease modifying drug for modeate to severe osteoarthritis of the knee (see NCT03122860 and NCT02536833). Phase 1 clinical results following a 24 week trial in knee OA are published [8]. |
| Mechanism Of Action and Pharmacodynamic Effects |
| In the joint, the Wnt pathway helps to control tissue homeostasis through regulation of mesenchymal stem cell differentiation into chondrocytes and osteoblasts, which is crucial for cartilage tissue repair and regeneration within joints. In OA joints, increased Wnt signaling leads to cartilage degradation [1]. Pharmacological modulation (inhibition) of Wnt signaling may provide a novel disease-modifying osteoarthritis drug (DMOAD), that will ameliorate cartilage dysregulation associated with OA [7]. Lorecivivint inhibits CLK2 and DYRK1A which are kinases involved in Wnt pathway modulation [3]. Inhibition of these two kinases does not affect β-catenin. It is reported that CLK2 inhibition induces early chondrogenesis and inhibition of DYRK1A enhances mature chondrocyte function. |
| Clinical Trials | |||||
| Clinical Trial ID | Title | Type | Source | Comment | References |
| NCT02536833 | A Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects | Phase 2 Interventional | Samumed LLC | ||
| NCT03122860 | A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis | Phase 2 Interventional | Samumed LLC | ||
| NCT02095548 | Phase 1, Dose Escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SM04690 in Moderate to Severe Knee Osteoarthritis (OA) | Phase 1 Interventional | Samumed LLC | Injection into the intra-articular knee joint was safe and well tolerated, and produced effects that were consistent with disease-modifying activity (at 24-week follow-up). There was no evidence of systemic exposure. | 8 |
