Zhou Guizhen, Zhou Chuan, Ma Xinyi, Xu Jiahang, Zhou Zehui, Xu Tianfeng, Zheng Mingyue, Zhang Sulin
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Expert Opin Ther Pat. 2024 Dec;34(12):1199-1213. doi: 10.1080/13543776.2024.2419825. Epub 2024 Oct 25.
SOS1 is a crucial guanine nucleotide exchange factor for KRAS. It facilitates the transition of KRAS from inactive GDP-bound state to active GTP-bound state. The activation of KRAS triggers downstream signaling pathways, promoting tumor initiation and progression. Inhibiting SOS1 to prevent KRAS activation is an effective strategy for treating tumors driven by KRAS.
This review identified patents claiming to be SOS1 inhibitors or SOS1-KRAS interaction modulators published between January 2022 and June 2024 using Cortellis Drug Discovery Intelligence. A total of 15 patent applications from 5 different applicants were assessed.
In KRAS-driven tumors, inhibiting SOS1 significantly affect cell proliferation and migration by modulating the RAS/MAPK and PI3K/AKT/mTOR signaling pathways. Since 2022, numerous patents for SOS1 inhibitors have been published. The majority of SOS1 inhibitors are currently in the preclinical phase of development, with only a few progressing to clinical trials. However, these inhibitors face significant challenges in clinical studies, including limited efficacy of monotherapies, safety concerns, and the necessity to enhance PK properties. Despite their excellent in vitro performance, SOS1 inhibitors must address issues related to safety, pharmacokinetics, and pharmacodynamics in clinical applications.
SOS1是KRAS的一种关键鸟嘌呤核苷酸交换因子。它促进KRAS从无活性的GDP结合状态转变为有活性的GTP结合状态。KRAS的激活触发下游信号通路，促进肿瘤的起始和进展。抑制SOS1以防止KRAS激活是治疗由KRAS驱动的肿瘤的有效策略。
本综述使用Cortellis药物发现情报系统，确定了2022年1月至2024年6月期间声称是SOS1抑制剂或SOS1-KRAS相互作用调节剂的专利。共评估了来自5个不同申请人的15项专利申请。
在KRAS驱动的肿瘤中，抑制SOS1通过调节RAS/MAPK和PI3K/AKT/mTOR信号通路，显著影响细胞增殖和迁移。自2022年以来，已发表了许多关于SOS1抑制剂的专利。目前，大多数SOS1抑制剂处于临床前开发阶段，只有少数进入临床试验。然而，这些抑制剂在临床研究中面临重大挑战，包括单一疗法疗效有限、安全问题以及增强药代动力学特性的必要性。尽管SOS1抑制剂在体外表现出色，但在临床应用中必须解决与安全性、药代动力学和药效学相关的问题。
