Design, synthesis, and evaluation of dual son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR) inhibitors for the treatment of cancers

  • Bioorg Chem. 2024 Sep 27:153:107833. doi: 10.1016/j.bioorg.2024.107833.
Yi Zeng  1 ,  Chenyang Huang  1 ,  Qiangqiang Hou  1 ,  Wenhua Jiang  1 ,  Jiaqi Cheng  1 ,  Xiaoxing Wu  2
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, and Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, and Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 39357170 DOI: 10.1016/j.bioorg.2024.107833
Abstract

The treatment of KRAS mutant tumors remains challenging and dual-targeted small-molecule drugs are considered to be innovative therapeutic alternatives. Herein, we discovered a series of SOS1 and EGFR dual inhibitors by employing a fused pharmacophore strategy and structural optimization. Notably, compound 4 exhibited potent SOS1 (IC50 = 8.3 nM) and EGFR (IC50 = 14.6 nM) inhibitory activities and markedly inhibited the proliferation of Other KRAS-mutant Cancer cell lines. Furthermore, Western blot analysis confirmed that compound 4 effectively reduced the level of downstream p-ERK. These results indicated that compound 4 could serve as a potential compound for treating KRAS mutant tumors.

Keywords
Dual inhibitor; EGFR; KRAS; SOS1.
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