Journal of medicinal chemistry · 2024
Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.
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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, Wang Zhiwei
Аннотация
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.