Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120, Vienna, Austria.
Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120, Vienna, Austria.
Curr Opin Chem Biol. 2021 Jun;62:109-118. doi: 10.1016/j.cbpa.2021.02.014. Epub 2021 Apr 10.
Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRAS inhibitors, but the vast majority of oncogenic KRAS alterations remain undrugged. The discovery of a druggable pocket on SOS1 has led to potent SOS1 inhibitors such as BI-3406. SOS1 inhibition leads to antiproliferative effects against all major KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers. In this review, we provide an overview of SOS1 function, its association with cancer and RASopathies, known SOS1 activators and inhibitors, and a future perspective is provided.
SOS 是一种鸟嘌呤核苷酸交换因子，能激活 KRAS 这一重要的细胞信号开关。SOS 能催化 KRAS（失活）到 KRAS（激活）构象的“跳动”，充当 KRAS（即癌症的“心脏”）的起搏器。SOS1 的激活突变常见于诺南综合征，而 KRAS 的致癌改变在七种人类癌症中驱动了 1。针对 KRAS 的选择性抑制剂已显示出良好的临床疗效，但绝大多数致癌 KRAS 改变仍然无法用药物治疗。SOS1 上发现一个可用药袋，导致了强效的 SOS1 抑制剂，如 BI-3406。SOS1 抑制导致针对所有主要 KRAS 突变体的抗增殖作用。首个 SOS1 抑制剂已进入 KRAS 突变型癌症的临床试验。在这篇综述中，我们概述了 SOS1 的功能、它与癌症和 RAS 病的关联、已知的 SOS1 激活剂和抑制剂，并提供了未来的展望。
