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

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Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-01 , DOI: 10.1021/acs.jmedchem.1c01774
Chuan Zhou ₁ , Zisheng Fan _{2,

3} , Zehui Zhou _{1,

4} , Yupeng Li ₅ , Rongrong Cui _{2,

3} , Chaoyi Liu ₁ , Guizhen Zhou _{2,

3} , Xingxing Diao ₆ , Hualiang Jiang _{2,

3,

4,

7} , Mingyue Zheng _{2,

3,

4,

7} , Sulin Zhang _{3,

4} , Tianfeng Xu _{1,

4,

7}

Affiliation

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.

中文翻译：

发现一流的基于激动剂的 SOS1 PROTACs 对携带各种 KRAS 突变的人类癌细胞有效

调节 SOS1 功能可能会导致靶向泛 KRAS 疗法。小分子SOS1抑制剂显示出良好的抗癌潜力，最先进的抑制剂BI 1701963目前正在进行I期临床研究。SOS1 激动剂为治疗癌症提供了新的机会；然而，潜在的机制仍然值得研究。我们在这里报告了通过将 VHL 配体连接到报道的 SOS1 激动剂而独特设计的第一个 SOS1 PROTAC 的发现，确保观察到的抑制活性来自降解剂。与激动剂本身相比，最佳化合物9d在各种 KRAS 驱动的癌细胞中诱导 SOS1 降解，并显示出优异的抗增殖活性。肿瘤异种移植研究清楚地显示了9d的有希望的抗肿瘤效力对抗人类肺癌。该研究为使用激动剂设计 SOS1 PROTACs 提供了很好的证据，并证明靶向 SOS1 降解代表了克服 KRAS 驱动的癌症的有效治疗策略。

更新日期：2022-03-01

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