Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK)

• Published in: Journal of medicinal chemistry Vol. 62; no. 7; pp. 3228 - 3250
• Main Authors: Watterson, Scott H, Liu, Qingjie, Beaudoin Bertrand, Myra, Batt, Douglas G, Li, Ling, Pattoli, Mark A, Skala, Stacey, Cheng, Lihong, Obermeier, Mary T, Moore, Robin, Yang, Zheng, Vickery, Rodney, Elzinga, Paul A, Discenza, Lorell, D’Arienzo, Celia, Gillooly, Kathleen M, Taylor, Tracy L, Pulicicchio, Claudine, Zhang, Yifan, Heimrich, Elizabeth, McIntyre, Kim W, Ruan, Qian, Westhouse, Richard A, Catlett, Ian M, Zheng, Naiyu, Chaudhry, Charu, Dai, Jun, Galella, Michael A, Tebben, Andrew J, Pokross, Matt, Li, Jianqing, Zhao, Rulin, Smith, Daniel, Rampulla, Richard, Allentoff, Alban, Wallace, Michael A, Mathur, Arvind, Salter-Cid, Luisa, Macor, John E, Carter, Percy H, Fura, Aberra, Burke, James R, Tino, Joseph A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-04-2019
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00167

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.