Wu Jialin, Li Xiaoxue, Wu Chengyong, Wang Yuxi, Zhang Jifa
Department of Neurology, Neuro-system and Multimorbidity Laboratory and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Eur J Med Chem. 2024 Mar 15;268:116282. doi: 10.1016/j.ejmech.2024.116282. Epub 2024 Feb 25.
The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling pathways, demonstrating potential anti-tumor effects. Predominantly, small molecule modulators that target SOS1 focus on a hydrophobic pocket within the CDC25 protein domain. The effectiveness of these modulators largely depends on their ability to interact with specific amino acids, notably Phe890 and Tyr884. This interaction is crucial for influencing the protein-protein interaction (PPI) between RAS and the catalytic domain of SOS1. Currently, most small molecule modulators targeting SOS1 are in the preclinical research phase, with a few advancing to clinical trials. This progression raises safety concerns, making the assurance of drug safety a primary consideration alongside the enhancement of efficacy in the development of SOS1 modulators. This review encapsulates recent advancements in the chemical categorization of SOS1 inhibitors and activators. It delves into the evolution of small molecule modulation targeting SOS1 and offers perspectives on the design of future generations of selective SOS1 small molecule modulators.
七号无翅型蛋白1（SOS1）鸟嘌呤核苷酸交换因子在真核生物物种中普遍存在，在促进RAS蛋白与GTP结合方面发挥着关键作用，从而调节细胞内RAS蛋白的激活。这种调节是涉及SOS1的反馈机制的一部分，这使得SOS1的激活剂和抑制剂都能够对下游信号通路进行控制，显示出潜在的抗肿瘤作用。主要地，靶向SOS1的小分子调节剂聚焦于细胞分裂周期蛋白25（CDC25）蛋白结构域内的一个疏水口袋。这些调节剂的有效性在很大程度上取决于它们与特定氨基酸相互作用的能力，特别是苯丙氨酸890（Phe890）和酪氨酸884（Tyr884）。这种相互作用对于影响RAS与SOS1催化结构域之间的蛋白质 - 蛋白质相互作用（PPI）至关重要。目前，大多数靶向SOS1的小分子调节剂处于临床前研究阶段，少数已进入临床试验。这种进展引发了安全问题，使得在SOS1调节剂的开发中，确保药物安全与提高疗效同样成为首要考虑因素。这篇综述总结了SOS1抑制剂和激活剂化学分类方面的最新进展。它深入探讨了靶向SOS1的小分子调节的演变，并对下一代选择性SOS1小分子调节剂的设计提出了见解。
