Son of sevenless homolog 1 (SOS1) plays a pivotal role as a molecular switch in the conversion of GDP-bound inactive KRAS to its active GTP-bound form, making SOS1 a promising therapeutic target for KRAS-driven cancers. While the most advanced SOS1 inhibitor has processed to phase I clinical trial, the exploration of novel SOS1 targeting strategies with distinct modes of action remains required. By employing proteolysis targeting chimera (PROTAC) technology, we obtained a series of new SOS1 degraders. The representative compound potently induced SOS1 degradation with a DC value of 209.4 nM and a D value of over 80 %. Mechanistic studies have illuminated that compound induced the formation of ternary complex involving SOS1-PROTAC-cereblon (CRBN) and triggered SOS1 protein degradation in a CRBN- and proteasome-dependent manner. In addition, compound effectively inhibited KRAS-RAF-ERK signalling, leading to the suppression of colony formation in KRAS-driven cancer cells. Overall, compound represents a new lead compound in the developing novel and potent therapy for the treatment of KRAS-driven cancers.

中文翻译：

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发现 LHF418 作为一种新的有效 SOS1 PROTAC 降解剂

Son of Sevenless 同源物 1 (SOS1) 作为分子开关，在 GDP 结合的非活性 KRAS 转化为活性 GTP 结合形式的过程中发挥着关键作用，这使得 SOS1 成为 KRAS 驱动的癌症的有希望的治疗靶点。虽然最先进的 SOS1 抑制剂已进入 I 期临床试验，但仍需要探索具有不同作用模式的新型 SOS1 靶向策略。通过采用蛋白水解靶向嵌合体（PROTAC）技术，我们获得了一系列新型SOS1降解剂。代表性化合物有效诱导 SOS1 降解，DC 值为 209.4 nM，D 值超过 80%。机理研究表明，该化合物诱导 SOS1-PROTAC-cereblon (CRBN) 三元复合物的形成，并以 CRBN 和蛋白酶体依赖性方式触发 SOS1 蛋白降解。此外，该化合物还能有效抑制 KRAS-RAF-ERK 信号传导，从而抑制 KRAS 驱动的癌细胞中集落的形成。总体而言，该化合物代表了一种新的先导化合物，用于开发治疗 KRAS 驱动的癌症的新型有效疗法。