Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer

  • J Med Chem. 2026 Jun 25;69(12):14437-14460. doi: 10.1021/acs.jmedchem.6c00196.
Xingchen Liu  1 ,  Yuzhou Xiao  2 ,  Yanmei Zhou  3 ,  Yaxin Teng  2 ,  Jiao Zou  2 ,  Yue Zhou  4 ,  Xinyu Fan  3 ,  Jinhua Zhao  2 ,  Jiahao Qiu  2 ,  Lingfeng Tang  2 ,  Zhiqiang Qiu  2 ,  Jing Xu  2 ,  Haoyue Luo  2 ,  Xiaodan Pan  2 ,  Wenjing Xu  2 ,  Bo Ren  2 ,  Kun Gou  2 ,  Chunqi Liu  2 ,  Yanyan Ren  2 ,  Jialing Song  2 ,  Ping Gao  2 ,  Xia Zhou  5 ,  Laiying Zhang  2 ,  Xinying Qian  2 ,  Jian Lei  3 ,  Xiaobo Cen  6  7 ,  Youfu Luo  2 ,  Yinglan Zhao  1  2
Affiliations
  • 1. Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 2. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 61004, China.
  • 4. Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5. Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, Department of Medicinal Chemistry, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
  • 6. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7. West China-Frantier PharmaTech Co. Ltd, Chengdu 610200, China.
PMID: 42247371 DOI: 10.1021/acs.jmedchem.6c00196
Abstract

The guanine nucleotide exchange factor SOS1 has emerged as an attractive therapeutic target for various KRAS-driven tumors. Herein, we employed a structure-based drug design strategy to develop a series of novel quinazoline-derived molecules. This effort yielded highly potent and selective SOS1 inhibitors, 78b and 78d, which displayed high SOS1 binding affinity, potently disrupted the SOS1-KRASG12C interaction, and inhibited nucleotide exchange in WT and multiple KRAS variants. Moreover, both compounds showed submicromolar 3D-antiproliferative activity across a panel of CRC cells, induced G1 phase arrest, and suppressed MAPK and PI3K signaling pathways. Furthermore, 78b and 78d demonstrated favorable safety profiles with no observed adverse effects at levels of 500 and 700 mg/kg, respectively. At doses of 60 mg/kg, they achieved significant tumor growth inhibition (75.1% and 86.2%, respectively) in HCT116 xenograft models without significant toxicity. Collectively, this study identifies potent drug candidates with strong pan-KRAS therapeutic efficacy against colorectal Cancer.

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