Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton?s Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases

被引：3

作者：

Guo, Yunhang ^{[1
]}

Hu, Nan ^{[2
]}

Liu, Ye ^{[3
]}

Zhang, Wei ^{[3
]}

Yu, Desheng ^{[3
]}

Shi, Gongyin ^{[3
]}

Zhang, Bo ^{[3
]}

Yin, Longbo ^{[2
]}

Wei, Min ^{[3
]}

Yuan, Xi ^{[4
]}

Luo, Lusong ^{[4
]}

Wang, Fan ^{[5
]}

Song, Xiaomin ^{[2
]}

Xin, Lei ^{[1
]}

Wei, Qiang ^{[1
]}

Li, Yong ^{[1
]}

Guo, Ying ^{[3
]}

Chen, Shuaishuai ^{[4
]}

Zhang, Taichang ^{[5
]}

Zhang, Shuo ^{[2
]}

Zhou, Xing ^{[3
]}

Zhang, Cuining ^{[6
]}

Su, Dan ^{[5
]}

Liu, Junhua ^{[1
]}

Cheng, Zhenzhen

Zhang, Jiye

Xing, Haimei ^{[4
]}

Sun, Hanzi ^{[3
]}

Li, Xin ^{[6
]}

Zhao, Yuan

He, Min

Wu, Yue ^{[5
]}

Guo, Yin

Sun, Xuebing ^{[3
]}

Tian, Alice ^{[6
]}

Zhou, Changyou ^{[1
]}

Young, Steve ^{[1
]}

Liu, Xuesong ^{[4
]}

Wang, Lai ^{[2
]}

Wang, Zhiwei ^{[1
]}

机构：

[1] BeiGene Beijing Co Ltd, Dept Med Chem, Beijing 102206, Peoples R China

[2] BeiGene Beijing Co Ltd, Dept Vivo Pharmacol, Beijing 102206, Peoples R China

[3] BeiGene Beijing Co Ltd, Dept Mol Sci, Beijing 102206, Peoples R China

[4] BeiGene Beijing Co Ltd, Dept Discovery Biol, Beijing 102206, Peoples R China

[5] BeiGene Beijing Co Ltd, Dept DMPK BA, Beijing 102206, Peoples R China

[6] BeiGene Beijing Co Ltd, Dept Nonclin Safety Assessment, Beijing 102206, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 06期

关键词：

PLATELET ACTIVATION; BTK; RECEPTOR; ZANUBRUTINIB; ARTHRITIS; DESIGN; TRIAL; MICE;

D O I：

10.1021/acs.jmedchem.2c01938

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4025 / 4044

页数：20

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