Department of Medicinal Chemistry, BeiGene (Beijing) Co., Ltd., Beijing 102206, P.R. China.
Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing 102206, P.R. China.
J Med Chem. 2023 Mar 23;66(6):4025-4044. doi: 10.1021/acs.jmedchem.2c01938. Epub 2023 Mar 13.
Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (-) leads to a series of highly selective BTK inhibitors, in which - is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, - has been declared a preclinical candidate. However, - showed an inferior toxicity profile compared to that of -.
布鲁顿酪氨酸激酶（BTK）在 B 细胞受体（BCR）介导的信号转导以及 Fc 受体（FcR）的下游信号通路中发挥重要作用。通过干扰 BCR 信号转导来靶向 BTK 治疗 B 细胞恶性肿瘤已被一些共价抑制剂在临床上验证，但激酶选择性不理想可能导致一些不良反应，这也使得自身免疫性疾病治疗的临床开发更具挑战性。从 zanubrutinib (-)开始的结构-活性关系（SAR）导致了一系列高度选择性的 BTK 抑制剂，其中 (-)位于 ATP 结合口袋中，与 ATP 的铰链结合相似，但对其他激酶（EGFR、Tec 等）具有高选择性。具有优异的药代动力学特征以及在肿瘤学和自身免疫性疾病模型中证明的疗效研究，(-)已被宣布为临床前候选药物。然而，(-)与 (-)相比表现出较差的毒性特征。
