作者: Guo, Yunhang ; Hu, Nan ; Liu, Ye ; Wei, Zhang ; Yu, Desheng ; Shi, Gongyin ; Zhang, Bo ; Yin, Longbo ; Wei, Min ; Yuan, Xi ; Luo, Lusong ; Wang, Fan ; Song, Xiaomin ; Wei, Qiang ; Li, Yong ; Guo, Ying ; Chen, Shuaishuai ; Zhang, Taichang ; Zhang, Shuo ; Zhou, Xing ; Su, Dan ; Liu, Junhua ; Cheng, Zhenzhen ; Zhang, Jiye ; Xing, Haimei ; Sun, Hanzi ; Zhao, Yuan ; Wu, Yue ; Guo, Yin ; Sun, Xuebing ; Zhou, Changyou ; Liu, Xuesong ; Wang, Lai ; Wang, Zhiwei
Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays an essential role in B cell receptor (BCR)-mediated signaling as well as downstream signaling pathway for Fc receptors (FcR). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clin. validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clin. development of autoimmune diseases more challenging. The structure-activity relationship (SAR) starting from Zanubrutinib (BGB-3111) leads to a series of high selective BTK inhibitors, in which BGB-8035 even maintains ATP-like binding mode but still exhibits high selectivity over other kinases including spares inhibition of EGFR and Tec (> 100-fold selective) and has a low potential for off-target related adverse effects in the treatment of oncol. or autoimmune disease. With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in mouse models of REC-1 mantle cell lymphoma (MCL) xenograft, collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA) and MRL/lpr spontaneous lupus, BGB-8035 has been declared a preclin. candidate.