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-x_L without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

中文翻译：

---

临床候选药物 Sonrotoclax (BGB-11417) 的发现，它是一种针对 WT 和 G101V 突变体 Bcl-2 的高效选择性抑制剂

Venetoclax 是一种 B 细胞淋巴瘤 2 (Bcl-2) 选择性抑制剂，用于治疗慢性淋巴细胞白血病的批准表明，抗凋亡蛋白 Bcl-2 是 B 细胞恶性肿瘤的药物靶点。然而，venetoclax 的有限效力不能在其他 Bcl-2 介导的恶性肿瘤（例如弥漫性大 B 细胞淋巴瘤）中产生强大、持久的临床益处，并且据报道多种复发性 Bcl-2 突变（例如 G101V）可介导耐药性长期治疗后使用venetoclax。在此，我们描述了新型 Bcl-2 抑制剂，对野生型 (WT) 和突变型 Bcl-2 均具有增强的效力。全面的结构优化产生了临床候选BGB-11417（化合物12e，sonrotoclax），它对WT Bcl-2和G101V突变体均表现出强大的体外和体内抑制活性，并且比不含Bcl-x L的Bcl-x L具有优异的选择性_。对细胞色素P450有明显的抑制作用。目前，BGB-11417正在进行单一疗法和联合治疗的II/III期临床评估。