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Abstract Number: 329

A Novel, Small Molecule Cyclin-Dependent Kinase 4/6 Inhibitor As the New Option for Treatment of Rheumatoid Arthritis

Hiroshi Takahashi1, Tsuyoshi Mizuno1, Toshimichi Nakamura1, Yuri Sakai1, Yumiko Muroga1, Kyohei Horie1, Naoki Hase1, Hitoshi Kohsaka2 and Tsuyoshi Kimura1, 1Teijin Pharma Limited, Hino,Tokyo, Japan, 2Department of Rheumatology, Graduate School of Medical and Dental Sciences,, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: kinase and rheumatoid arthritis (RA)

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Session Information

Title: Rheumatoid Arthritis - Animal Models

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

H. Takahashi,

Teijin Pharma Limited,

3;

T. Mizuno,

Teijin Pharma Limited ,

3;

T. Nakamura,

Teijin Pharma Limited,

3;

Y. Sakai,

Teijin Pharma Limited,

3;

Y. Muroga,

Teijin Pharma Limited,

3;

K. Horie,

Teijin Pharma Limited,

3;

N. Hase,

Teijin Pharma Limited,

3;

H. Kohsaka,

Teijin Pharma Limited,

2,

Mitsubishi Tanabe Pharma Corporation,

2,

Takeda Pharmaceutical Company Limited,

2,

Bristol-Myers Squibb Company,

2,

ONO PHARMACEUTICAL CO.,LTD.,

2,

Eisai Co.,Ltd.,

2,

Pfizer Inc.,

2,

Actelion Pharmaceuticals Ltd.,

2,

CHUGAI PHARMACEUTICAL CO.,LTD.,

2,

Astellas Pharma Inc.,

2,

Santen Pharmaceutical Co.,Ltd.,

2,

DAIICHI SANKYO COMPANY,LIMITED,

2,

Nippon Kayaku Co.,Ltd.,

2,

AbbVie Inc.,

2,

CHUGAI PHARMACEUTICAL CO.,LTD.,

5,

Bristol-Myers Squibb Company,

5,

UCB Inc.,

5,

Astellas Pharma Inc.,

5,

Nippon Shinyaku Co., Ltd.,

5,

Actelion Pharmaceuticals Ltd.,

5,

AbbVie Inc.,

5,

Pfizer Inc.,

5,

Kowa Company,Ltd.,

5,

ONO PHARMACEUTICAL CO.,LTD.,

5,

ASAHI KASEI PHARMA CORPORATION,

5,

Japan Blood Products Organization,

5,

Mitsubishi Tanabe Pharma Corporation,

5,

Santen Pharmaceutical Co.,Ltd.,

5,

Teijin Pharma Limited,

5;

T. Kimura,

Teijin Pharma Limited,

3.

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