American Chemical Society
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Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase for B‑Cell Malignancies and Autoimmune Diseases

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posted on 2023-03-13, 15:39 authored by Yunhang Guo, Nan Hu, Ye Liu, Wei Zhang, Desheng Yu, Gongyin Shi, Bo Zhang, Longbo Yin, Min Wei, Xi Yuan, Lusong Luo, Fan Wang, Xiaomin Song, Lei Xin, Qiang Wei, Yong Li, Ying Guo, Shuaishuai Chen, Taichang Zhang, Shuo Zhang, Xing Zhou, Cuining Zhang, Dan Su, Junhua Liu, Zhenzhen Cheng, Jiye Zhang, Haimei Xing, Hanzi Sun, Xin Li, Yuan Zhao, Min He, Yue Wu, Yin Guo, Xuebing Sun, Alice Tian, Changyou Zhou, Steve Young, Xuesong Liu, Lai Wang, Zhiwei Wang
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 (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 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, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.