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

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.

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