2. Academic Validation
  3. Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer

Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer

  • Eur J Med Chem. 2024 Jul 26:277:116711. doi: 10.1016/j.ejmech.2024.116711.
Xiaoxue Wang 1,  Zhongxiang Qin 2,  Wenrui Qiu 3,  Kejia Xu 2,  Yuting Bai 2,  Beilei Zeng 4,  Yakun Ma 2,  Shuang Yang 5,  Yi Shi 6,  Yan Fan 7
Affiliations

Affiliations

  • 1 Eye Institute, Nankai University, 94 Weijin Road, Tianjin, 300071, China; School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
  • 2 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
  • 3 Tianjin Normal University, No.393, Extension of Bin Shui West Road, Xi Qing District, Tianjin, 300387, China.
  • 4 Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, China.
  • 5 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yangshuang@nankai.edu.cn.
  • 6 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yishi@nankai.edu.cn.
  • 7 Eye Institute, Nankai University, 94 Weijin Road, Tianjin, 300071, China; School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yanfan@nankai.edu.cn.
PMID: 39094277 DOI: 10.1016/j.ejmech.2024.116711
Abstract

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 μM) but had a weak effect on EGFRWT (IC50 = 1.05 μM). 11eg significantly inhibited the proliferation of the non-small cell lung Cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 μM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing Apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.

Keywords

C797S; EGFR; Inhibitor; NSCLC.

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