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).
Scott H WattersonQingjie LiuMyra Beaudoin BertrandDouglas G BattLing LiMark A PattoliStacey SkalaLihong ChengMary T ObermeierRobin MooreZheng YangRodney VickeryPaul A ElzingaLorell DiscenzaCelia D'ArienzoKathleen M GilloolyTracy L TaylorClaudine PulicicchioYifan ZhangElizabeth HeimrichKim W McIntyreQian RuanRichard A WesthouseIan M CatlettNaiyu ZhengCharu ChaudhryJun DaiMichael A GalellaAndrew J TebbenMatt PokrossJianqing LiRulin ZhaoDaniel SmithRichard RampullaAlban AllentoffMichael A WallaceArvind MathurLuisa Salter-CidJohn E MacorPercy H CarterAberra FuraJames R BurkeJoseph A TinoPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- low dose
- rheumatoid arthritis
- signaling pathway
- systemic lupus erythematosus
- disease activity
- small molecule
- immune response
- open label
- binding protein
- oxidative stress
- acute lymphoblastic leukemia
- clinical trial
- dendritic cells
- pi k akt
- systemic sclerosis
- ankylosing spondylitis
- single cell
- interstitial lung disease
- replacement therapy