Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

调控SOS1的功能有望开发靶向泛KRAS治疗策略。小分子SOS1抑制剂展现出良好的抗癌潜力，其中进展最快的抑制剂BI 1701963目前正处于I期临床研究阶段。SOS1激动剂为癌症治疗带来了新的机遇，但其背后的具体作用机制仍有待进一步探究。本研究报道了首个通过将VHL配体（VHL ligand）与已报道的SOS1激动剂偶联而独特设计的SOS1蛋白水解靶向嵌合体（PROTACs），可确保所观测到的抑制活性来自降解剂的作用。最优化合物9d可在多种KRAS驱动的癌细胞中诱导SOS1降解，且相较于其原型激动剂，展现出更优异的抗增殖活性。肿瘤异种移植实验明确证实了9d对人肺癌具有良好的抗肿瘤活性。本研究为利用激动剂设计SOS1蛋白水解靶向嵌合体提供了坚实的证据支撑，并证实靶向SOS1降解是攻克KRAS驱动型癌症的有效治疗策略。