Date: Sunday, October 21, 2018
Session Title: Rheumatoid Arthritis – Animal Models Poster
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: The pathogenesis of rheumatoid arthritis (RA) is characterized by the infiltration of immune cells into the synovial tissues and the hypertrophy of synovial fibroblasts, resulting in the destruction of bone and joint. Given the pathogenesis, the ideal therapeutic strategy for RA is to target both immune cells/pro-inflammatory cytokines and synovial fibroblasts. However, there is no drug targeting the latter, whereas anti-immune cell/cytokine drugs such as methotrexate, biologics and JAK inhibitors are the mainstay in the current treatment of RA. To date we found Compound X, a highly selective and potent inhibitor against cyclin-dependent kinase (CDK) 4/6, which is a key regulator of cell cycle. Compound X inhibits the proliferation and matrix metalloproteinase 3 (MMP-3) secretion in synovial fibroblasts from RA patients, and the progression of arthritis in adjuvant-induced arthritic rats. To determine the potential of CDK4/6 inhibitor targeting the hypertrophy of synovial fibroblasts, as development candidate for RA treatment, we examined the efficacy of Compound X using preclinical animal models.
Methods: To examine the effects of Compound X on arthritis, collagen-induced arthritis (CIA) was used. To induce arthritis, DBA/1 mice were administered twice with intradermal injection of type II collagen at the tail root on Day0 and 3. Compound X was orally administered twice daily for 19 days. To examine the effect of Compound X on arthritis after the activation of immune system, anti-type II collagen antibody-induced arthritis (CAIA) model was used. DBA/1 mice were intraperitoneally injected with anti-type II collagen antibody on Day0 and LPS on Day3. Compound X was orally administered twice daily for 18 days. Arthritic score over time, serum MMP-3 level and bone destruction were examined in CIA and CAIA mice. In addition, MMP-3 expression in the joint and anti-type II collagen IgG level were examined in CIA mice.
Results: CIA mice developed the arthritis and showed gradual increase in arthritic score. Compound X significantly suppressed the progression of arthritis in a dose-dependent manner. Serum MMP-3 level in CIA mice was increased compared with Intact animals, which is consistent with MMP-3 expression in the joint. Compound X suppressed serum MMP-3 level and tissue expression. CIA mice with Compound X had lower incidence of bone destruction than CIA mice. Compound X did not reduce type II collagen IgG level, suggesting that Compound X has no impact on the immune system. Consistent with this, Compound X also suppressed the progression of arthritis in CAIA mice without immunization. Bone erosion score was reduced by Compound X, and correlated to arthritic score.
Conclusion: Compound X suppressed RA-related events such as the progression of the arthritis, increased serum MMP-3 and bone destruction. These results suggest that CDK4/6 inhibitor can be the first-in-class drug which targets the hypertrophy of synovial fibroblasts.
To cite this abstract in AMA style:Tsujimoto S, Horie K, Mashiko T, Nomura J, Kobayashi T. Cyclin-Dependent Kinase 4/6 Inhibitor: A Promising Development Candidate Targeting Synovial Hypertrophy for Rheumatoid Arthritis Treatment [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/cyclin-dependent-kinase-4-6-inhibitor-a-promising-development-candidate-targeting-synovial-hypertrophy-for-rheumatoid-arthritis-treatment/. Accessed May 30, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cyclin-dependent-kinase-4-6-inhibitor-a-promising-development-candidate-targeting-synovial-hypertrophy-for-rheumatoid-arthritis-treatment/