Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, Son of Sevenless homologue 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

中文翻译：

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基于 Cereblon 的 SOS1 双功能降解剂 BTX-6654，针对多个 KRAS 突变并抑制肿瘤生长

估计 25% 的癌症是由癌基因 KRAS 内的突变引起的。目前只有等位基因特异性 KRAS G12C 抑制剂可用，并且与获得性耐药的出现有关，部分原因是上游途径重新激活。鉴于其在 KRAS 激活中的上游作用，Son of Sevenless 同源物 1 (SOS1) 已成为一个有吸引力的治疗靶点。以 SOS1 为目标进行降解的药物可能代表一种潜在的泛 KRAS 模式，能够规避某些获得性耐药机制。在这里，我们报告了两种基于 SOS1 cereblon 的双功能降解剂 BTX-6654 和 BTX-7312（基于 cereblon 的双功能 SOS1 降解剂）的开发。两种化合物均表现出有效的目标依赖性和特异性 SOS1 降解作用。BTX-6654 和 BTX-7312 减少下游信号标记 pERK 和 pS6，并在含有各种 KRAS 突变的细胞中表现出抗增殖活性。在两个 KRAS G12C 异种移植模型中，BTX-6654 以剂量依赖性方式降解 SOS1，与肿瘤生长抑制相关，此外还表现出与 KRAS 和 MEK 抑制剂的协同作用。总而言之，BTX-6654 为 KRAS 驱动的癌症中双功能 SOS1 降解剂的单药和联合使用提供了临床前概念证明。