Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton , New Jersey 08543 , United States.
J Med Chem. 2019 Apr 11;62(7):3228-3250. doi: 10.1021/acs.jmedchem.9b00167. Epub 2019 Mar 29.
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.
布鲁顿酪氨酸激酶（BTK）是一种非受体酪氨酸激酶，属于 Tec 激酶家族成员，是 B 细胞受体（BCR）介导的信号转导所必需的。BTK 在单核细胞中的 Fcγ 受体、粒细胞中的 Fcε 受体和破骨细胞中的 RANK 受体的下游信号通路中也起着关键作用。因此，BTK 的药理学抑制有望为类风湿关节炎和狼疮等自身免疫性疾病的临床治疗提供一种有效的策略。本文将概述我们确定一种共价、不可逆 BTK 抑制剂的策略的演变，该抑制剂具有内在的效力、选择性和药代动力学特性，在极低剂量下能在体内迅速失活。由于具有优异的体内疗效和非常理想的耐受性特征，5a（branebrutinib，BMS-986195）已进入临床研究。
