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Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
Journal of Medicinal Chemistry  (IF7.446),  Pub Date : 2019-08-05, DOI: 10.1021/acs.jmedchem.9b00687
Yunhang Guo,Ye Liu,Nan Hu,Desheng Yu,Changyou Zhou,Gongyin Shi,Bo Zhang,Min Wei,Junhua Liu,Lusong Luo,Zhiyu Tang,Huipeng Song,Yin Guo,Xuesong Liu,Dan Su,Shuo Zhang,Xiaomin Song,Xing Zhou,Yuan Hong,Shuaishuai Chen,Zhenzhen Cheng,Steve Young,Qiang Wei,Haisheng Wang,Qiuwen Wang,Lei Lv,Fan Wang,Haipeng Xu,Hanzi Sun,Haimei Xing,Na Li,Wei Zhang,Zhongbo Wang,Guodong Liu,Zhijian Sun,Dongping Zhou,Wei Li,Libin Liu,Lai Wang,Zhiwei Wang

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.