1. Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2
- Author
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Guo, Yunhang, Xue, Hai, Hu, Nan, Liu, Ye, Sun, Hanzi, Yu, Desheng, Qin, Ling, Shi, Gongyin, Wang, Fan, Xin, Lei, Sun, Weihua, Zhang, Fan, Song, Xiaomin, Li, Shuran, Wei, Qiang, Guo, Ying, Li, Yong, Liu, Xiaoxin, Chen, Shuaishuai, Zhang, Taichang, Wu, Yue, Su, Dan, Zhu, Yutong, Xu, Aiying, Xu, Haipeng, Yang, Shasha, Zheng, Zhijun, Liu, Junhua, Yang, Xuefei, Yuan, Xi, Hong, Yuan, Sun, Xuebing, Guo, Yin, Zhou, Changyou, Liu, Xuesong, Wang, Lai, and Wang, Zhiwei
- 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 vitroand in vivoinhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xLwithout obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.
- Published
- 2024
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