Discovery of a potent and orally available SOS1 inhibitor with antitumor efficacy in KRAS-mutant colorectal cancers

  • Bioorg Chem. 2026 Jul 5:175:109823. doi: 10.1016/j.bioorg.2026.109823.
Xingchen Liu  1 ,  Yuzhou Xiao  2 ,  Lingfeng Tang  2 ,  Yanmei Zhou  3 ,  Jinhua Zhao  2 ,  Jiao Zou  2 ,  Yue Zhou  4 ,  Yaxin Teng  2 ,  Xinyu Fan  3 ,  Jiahao Qiu  2 ,  Jing Xu  2 ,  Zhiqiang Qiu  2 ,  Kun Gou  2 ,  Haoyue Luo  2 ,  Yanyan Ren  2 ,  Xiaodan Pan  2 ,  Jialing Song  2 ,  Wenjing Xu  2 ,  Ping Gao  2 ,  Bo Ren  2 ,  Xia Zhou  5 ,  Xiaobo Cen  6 ,  Youfu Luo  7 ,  Yinglan Zhao  8
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; West China-Frantier PharmaTech Co., Ltd., Chengdu 610200, China.
  • 7. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 8. Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 41950716 DOI: 10.1016/j.bioorg.2026.109823
Abstract

As a key guanine nucleotide exchange factor, SOS1 is an attractive therapeutic target for KRAS-driven colorectal Cancer. In this study, based on the co-crystal structure of SOS1 in complex with BI-68BS, we developed a high-affinity fluorescent tracer TRR2 (KD = 0.134 μM), and established a robust fluorescence polarization assay for the profiling of SOS1 inhibitors. Subsequent structure-based optimization yielded a series of SOS1 inhibitors, among which SL43 emerged as the most promising candidate. SL43 demonstrated superior binding affinity to SOS1 (KD = 0.16 μM), potently disrupted the SOS1-KRASG12C interaction (IC50 = 13.0 nM) and broadly inhibited SOS1-mediated nucleotide exchange on multiple KRAS mutants (G12C, G12V and G12D; IC50 = 13.4-29.1 nM). Biologically, SL43 exhibited potent and selective antiproliferative activity against KRAS-mutant colorectal Cancer cells (IC50 = 0.028-0.238 μM), achieving over 100-fold selectivity over KRAS wild-type cells. in Balb/c mice, SL43 displayed a favorable profile with a moderate half-life (T1/2 = 4.6 h) and high oral bioavailability (F = 56.8%). In an HCT116 xenograft model, oral administration of SL43 (20 and 40 mg/kg) also significantly suppressed tumor growth (TGI = 57.2% and 74.9%, respectively), outperforming MRTX0902 (60 mg/kg, TGI = 47.1%) with no observable systemic toxicity. In conclusion, SL43 represents a potent and orally bioavailable SOS1 inhibitor that effectively suppresses KRAS signaling and exerts strong antitumor efficacy, highlighting its potential as a promising candidate for KRAS-mutant colorectal Cancer.

Keywords
Colorectal cancer; KRAS-mutant; SOS1 inhibitor; Structure-activity relationship.
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