Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2

  • J Med Chem. 2024 May 23;67(10):7836-7858. doi: 10.1021/acs.jmedchem.4c00027.
Yunhang Guo ,  Hai Xue ,  Nan Hu ,  Ye Liu ,  Hanzi Sun ,  Desheng Yu ,  Ling Qin ,  Gongyin Shi ,  Fan Wang ,  Lei Xin ,  Weihua Sun ,  Fan Zhang ,  Xiaomin Song ,  Shuran Li ,  Qiang Wei ,  Ying Guo ,  Yong Li ,  Xiaoxin Liu ,  Shuaishuai Chen ,  Taichang Zhang ,  Yue Wu ,  Dan Su ,  Yutong Zhu ,  Aiying Xu ,  Haipeng Xu ,  Shasha Yang ,  Zhijun Zheng ,  Junhua Liu ,  Xuefei Yang ,  Xi Yuan ,  Yuan Hong ,  Xuebing Sun ,  Yin Guo ,  Changyou Zhou ,  Xuesong Liu ,  Lai Wang ,  Zhiwei Wang
PMID: 38695063 DOI: 10.1021/acs.jmedchem.4c00027
Abstract

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of Chronic Lymphocytic Leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious Cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.