Background/Purpose The pathogenesis of rheumatoid arthritis (RA) is characterized by infiltration of immune cells to the synovial tissues and their hyperplasia. Therapeutic strategies to inhibit proinflammatory cytokines or immune cells with biological agents and methotrexate are the mainstay in the current treatment of RA. However, they cannot induce complete remission in all of the patients. Combination therapy of two biologics such as etanercept and abatacept failed to show the synergistic effects. Cyclin-dependent kinases (CDK) are key regulators of the cell cycle progression, and several CDK inhibitors have been developed for treatment of cancer. Recently, it was reported that cell cycle inhibition of synovial fibroblasts with a small molecule CDK4/6 inhibitor ameliorated progression of arthritis without attenuating acquired immune responses in an animal model of RA. Although CDK4/6 is thus an attractive target for treatment of RA, its inhibitors have not yet been developed for clinical use in RA treatment. In this study, we show that we have developed a novel and potent CDK4/6 inhibitor, Compound T and its derivatives for RA treatment. We examined Compound T for its anti-arthritic effects in monotherapy and in combination therapy with TNF blockade in animal models of RA. 

Methods Novel synthetic compounds were evaluated in kinase assays to determine in vitro CDK4/6 inhibitory activity and selectivity for CDKs and other kinases. The effects of these compounds on cell cycle were tested by the SubG1 method. Pharmacokinetic (PK) studies and hERG channel binding assay were performed to determine PK and safety profiles of the test compounds. In vivo efficacy of Compound T was tested in collagen induced arthritis (CIA) as well as anti-collagen antibody induced arthritis (CAIA) of mice. Compound T was orally administered to both models to see the effects on the arthritis score. The effect of combination treatment of Compound T with etanercept was tested in the CAIA model.

Results Compound T inhibited CDK4 and 6 potently (IC50 is about 1 nM) and selectively to other kinases in the cell free assay. Compound T inhibited cell cycle at the G0/G1 phase without inducing cell death in the cell based assay. Oral administration of Compound T alone suppressed the arthritis score, compared to vehicle treatment, in the CAIA and CIA models. In the CAIA model, combination of oral Compound T with intraperitoneal etanercept synergistically suppressed the progression of arthritis compared to monotheray with Compound T or with etanercept at maximum effective dose. In hERG binding assay, Compound T had binding activity at the high concentration range, but several compounds among its derivatives showed  low binding affinity against hERG.

Conclusion Compound T we synthesized is a potent inhibitor of CDK4/6 and selective to other kinases. Oral treatment with Compound T suppressed the arthritis score in both CAIA and CIA models of mice. CDK4/6 inhibitors should offer a new option for better treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-small-molecule-cyclin-dependent-kinase-46-inhibitor-as-the-new-option-for-treatment-of-rheumatoid-arthritis/