Background/Purpose: The pathogenesis of rheumatoid arthritis (RA) is characterized by the infiltration of immune cells into the synovial tissues and the excessive proliferation of synovial fibroblasts, resulting in synovial hyperplasia (pannus formation) and subsequent destruction of the bones and joints. Therapeutic strategies to inhibit pro-inflammatory cytokines or immune cells with methotrexate and biologics are the mainstay in the current treatment of RA. However, they cannot induce complete clinical remission in all of the patients. Cyclin-dependent kinase (CDK) 4/6 are key regulators in cell cycle, and its inhibitors have been reported to attenuate the proliferation of synovial fibroblasts and the progression of arthritis without inhibiting acquired immune responses in mouse RA models. To provide novel therapeutic option to inhibit the synovial hyperplasia, we performed the screening for CDK4/6 inhibitors and found out Compound X with high potency and selectivity for CDK4/6. Here we show the pharmacological and safety profiles of Compound X.

Methods: In vitro activities of Compound X were examined in kinase assays to determine the inhibitory activity against CDK4/6 and the selectivity to other kinases. In vivo efficacies of Compound X were examined in collagen-induced arthritis (CIA) of mice. Combination efficacy of Compound X and etanercept was examined in anti-collagen antibody-induced arthritis (CAIA) of mice. Adjuvant-induced arthritis (AIA) in rats was performed to determine the safety margin of Compound X. Compound X was orally administrated twice daily for 19 days in mice and once daily for 3 weeks in rats, respectively. A toxicological profiling of Compound X was conducted with 4-week repeat dose studies in rats and monkeys. Telemetry study in monkeys and proarrhythmia study in human iPS cell-derived cardiomyocytes were conducted to evaluate the risk of the cardiovascular system.

Results: Compound X showed dose-dependent inhibition of the progression of arthritis and bone destruction in the CIA mice. The serum MMP-3 level was decreased by Compound X, which is consistent with the finding that inhibition of MMP-3 secretion by Compound X in synovial fibroblasts from RA patients. Furthermore, combination of Compound X with etanercept suppressed arthritic score and MMP-3 level more than monotherapy with Compound X or etanercept at the most effective dose. Whereas myelosuppression was observed at 120 mg/kg of Compound X in the AIA rats, the best efficacy in arthritic score was observed at 15 mg/kg. Four-week general toxicity studies in rats and monkeys demonstrated that Compound X is well-tolerated and has no critical concerns. In addition, telemetry study in monkeys and proarrhythmia study using human iPS-derived cardiomyocytes revealed a low risk of the cardiovascular system.

Conclusion: Compound X is an orally available CDK4/6 inhibitor and a promising candidate for development for RA treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacological-and-safety-profiles-of-cyclin-dependent-kinase-46-inhibitor-candidate-for-development-as-rheumatoid-arthritis-therapeutic-option/