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OP0075 TAS5315, A Novel Bruton's Tyrosine Kinase (BTK) Inhibitor, Demonstrates Potent Efficacy in Mouse Collagen-Induced Arthritis Model
  1. F. Hosoi1,
  2. S. Iguchi2,
  3. Y. Yoshiga1,
  4. R. Kaneko1,
  5. Y. Nakachi1,
  6. D. Akasaka1,
  7. K. Yonekura3,
  8. Y. Iwasawa3,
  9. E. Sasaki1,
  10. T. Utsugi3
  1. 1Drug Discovery & Development II
  2. 2Medicinal Chemistry
  3. 3Taiho Pharmaceutical, Tsukuba, Japan


Background Bruton's tyrosine kinase (BTK) is a member of the Tec family kinases, and is expressed in B cells, monocytes/macrophages, mast cells, basophils and osteoclast1,2. BTK is a critical effector molecule that activates B cell receptor signaling pathway in B cells and Fc-γ receptor signaling pathway in macrophages3. In osteoclast, RANKL (receptor activator of NF-kB ligand) binds to its receptor RANK, and induces differentiation and bone resorption of osteoclast through BTK-PLCγ signaling pathway. These various effector cells are reported to be associated with disease progression of rheumatoid arthritis4,5. Therefore, BTK would be an attractive target for a therapeutic agent in autoimmune disease such as rheumatoid arthritis (RA). We discovered a novel synthesized compound which inhibits BTK with a highly selectivity.

Objectives We report characteristics of a highly selective and potent BTK inhibitor, TAS5315, in vitro and in vivo models for RA.

Methods The kinase selectivity of TAS5315 was evaluated in a series of biochemical assays. The expression of CD69, a lymphocyte activation marker, stimulated by anti-IgM in the mouse splenic B cells was measured using flow cytometry. The bone resorption activity of mouse osteoclast was evaluated using osteoclast culture kit. Male DBA/1 mice were injected on day-27 and-6 with an emulsion of complete Freund's adjuvant and bovine type II collagen. TAS5315 (0.05, 0.1, 0.2 and 0.4 mg/kg) was administrated orally once daily for 15 consecutive days.

Results TAS5315 showed a potent inhibitory activity against anti-IgM-induced phosphorylation of BTK with an IC50 in sub nmol/L range. TAS5315 also inhibited only 4 kinases (TEC, BMX, TXK and ITK) out of 276 off-target kinases with high inhibitory activity (over 80% at 100 nmol/L). The up-regulation of CD69 on stimulated mouse splenic B cells was suppressed by TAS5315 in a dose-dependent manner (IC50 =0.2 nmol/L). In pit formation assay, TAS5315 also inhibited bone resorption activity of osteoclast in a dose-dependent manner (IC50 =2.2 nmol/L). In a mouse collagen-induced arthritis model, TAS5315 dose-dependently and significantly decreased the clinical score in arthritic mice compared with that in vehicle-treated mice, with an ED50 value of 0.12 mg/kg. The treatment group with TAS5315 (0.4 mg/kg) completely ameliorated arthritic symptoms on day 14. All four paws of CIA mice were then examined by histopathological analysis. TAS5315-treated mice had a marked reduction in the severity of inflammation, pannus, cartilage destruction and bone destruction in a dose-dependent manner. In the micro CT analysis of hind paws of CIA mice, TAS5315 (1mg/kg)-treated mice showed a remarkable recovery of bone mineral density compared with vehicle-treated mice.

Conclusions Our study demonstrates that TAS5315 is a highly selective BTK inhibitor and has significant efficacy in the mouse CIA model. These data suggests that TAS5315 could be a promising new therapeutic agent for RA.


  1. Curr Opin Immunol. 2000;12, 282-288,

  2. Int Arch Allergy Immunol. 2004; 134, 65-78,

  3. Rheumatology (Oxford). 2013; 52, 1155-1162,

  4. Arthritis Res Ther. 2011; 134, 3380-3391,

  5. Nat Rev Immunol. 2007; 7, 191-201

Disclosure of Interest F. Hosoi Employee of: Taiho pharmaceutical co. ltd., S. Iguchi Employee of: Taiho pharmaceutical co. ltd., Y. Yoshiga Employee of: Taiho pharmaceutical co. ltd., R. Kaneko Employee of: Taiho pharmaceutical co. ltd., Y. Nakachi Employee of: Taiho pharmaceutical co. ltd., D. Akasaka Employee of: Taiho pharmaceutical co. ltd., K. Yonekura Employee of: Taiho pharmaceutical co. ltd., Y. Iwasawa Employee of: Taiho pharmaceutical co. ltd., E. Sasaki Employee of: Taiho pharmaceutical co. ltd., T. Utsugi Employee of: Taiho pharmaceutical co. ltd.

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