1. Academic Validation
  2. 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)

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)

  • J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167.
Scott H Watterson 1 Qingjie Liu 1 Myra Beaudoin Bertrand 1 Douglas G Batt 1 Ling Li 1 Mark A Pattoli 1 Stacey Skala 1 Lihong Cheng 1 Mary T Obermeier 1 Robin Moore 1 Zheng Yang 1 Rodney Vickery 1 Paul A Elzinga 1 Lorell Discenza 1 Celia D'Arienzo 1 Kathleen M Gillooly 1 Tracy L Taylor 1 Claudine Pulicicchio 1 Yifan Zhang 1 Elizabeth Heimrich 1 Kim W McIntyre 1 Qian Ruan 1 Richard A Westhouse 1 Ian M Catlett 1 Naiyu Zheng 1 Charu Chaudhry 1 Jun Dai 1 Michael A Galella 1 Andrew J Tebben 1 Matt Pokross 1 Jianqing Li 1 Rulin Zhao 1 Daniel Smith 1 Richard Rampulla 1 Alban Allentoff 1 Michael A Wallace 1 Arvind Mathur 1 Luisa Salter-Cid 1 John E Macor 1 Percy H Carter 1 Aberra Fura 1 James R Burke 1 Joseph A Tino 1
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543 , United States.
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112161
    99.82%, BTK Inhibitor
    Btk