Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K_i values of <1 nM and inhibits cancer cell growth with IC₅₀ values of 1–2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.

中文翻译：

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一种强效且高效的 Bcl-2/Bcl-xL 抑制剂

我们之前报道的 Bcl-2/Bcl-xL 抑制剂4有效抑制了肿瘤生长，但未能在体内实现完全消退。我们现在对其吡咯核心结构进行了广泛的修改，最终发现了32 (BM-1074)。化合物32与 Bcl-2 和 Bcl-xL 蛋白结合，K _i值 <1 nM，并在四种对强效和特异性 Bcl-敏感的小细胞肺癌细胞系中抑制癌细胞生长，IC ₅₀值为 1–2 nM 2/Bcl-xL 抑制剂。化合物32能够以耐受良好的剂量方案在体内实现快速、完全和持久的肿瘤消退。化合物32 是迄今为止报道的最有效和最有效的 Bcl-2/Bcl-xL 抑制剂。