A study from Xiaojing Wang discovered and identified a novel Btk inhibitor G-744 that has potential to treat arthritis.

Bruton’s tyrosine kinase (Btk) plays an indispensable role in the function of B cells and myeloid cells. Therefore, Btk has become an attractive target for immunological disorders treatment, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and B-cell lymphomas. It’s encouraging that some Btk inhibitors have been marketed. Ibrutinib, a Btk inhibitor, has been recently approved for treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia.

In the study, the authors verified G-744 as a highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

Besides, in vitro, G-744 is a Btk inhibitor with an IC50 of 2 nM.

In pharmacokinetic experiments, G-744 exhibited low to moderate clearance in four preclinical species. And G-744 showed excellent oral activity in animal models.

In addition, in female Lewis rat based CIA models, the authors treated rats with G-744 by oral administration daily, with doses of 6.25, 12.25, 25 mg/kg. As a result, all three doses resulted in a significant dose-dependent inhibition of ankle thickness between day 10 and day 17 (onset of increase in ankle diameter on day 9). In other words, G-744 (6.25/12.25/25 mg/kg, p.o., b.i.d., daily) protected Lewis rats from collagen-induced arthritis dose-dependently.

But until now, in vitro experiments are still lacked. G-744 need to be verified further and further.

Wang X, et al. Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties. ACS Med Chem Lett. 2017 May 3;8(6):608-613.