Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

  • Bioorg Med Chem Lett. 2025 Sep 1:125-126:130282. doi: 10.1016/j.bmcl.2025.130282.
Yating Chen  1 ,  Qiupei Liu  2 ,  Xianghui Meng  3 ,  Wenxu Cao  4 ,  Lihui Duo  5 ,  Xiaorong Song  6 ,  Xiangchun Shen  1 ,  Sze Shin Low  5 ,  Wan Yong Ho  7 ,  Bencan Tang  8 ,  Pengli Zhang  9 ,  Hua Xie  10 ,  Guoqin Xia  11
Affiliations
  • 1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550014, China.
  • 2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo 315100, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210000, China.
  • 4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 101408, China.
  • 5. Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo 315100, China.
  • 6. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 7. Faculty of Medicine and Health Sciences, University of Nottingham Malaysia, Semenyih 43500, Malaysia.
  • 8. Faculty of Science and Engineering, The University of Nottingham Ningbo China, Ningbo 315100, China. Electronic address: [email protected].
  • 9. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: [email protected].
  • 10. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: [email protected].
  • 11. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550014, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 101408, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210000, China. Electronic address: [email protected].
PMID: 40383301 DOI: 10.1016/j.bmcl.2025.130282
Abstract

The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and Akt in the NCI-H358 Cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven Cancer.

Keywords
KRAS mutation; Resistance; SOS1 inhibitor; SOS1-KRAS interaction.
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