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

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

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: wu_xiaoxing@cpu.edu.cn.
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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