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Discovery of Novel Fourth-Generation EGFR Inhibitors to Overcome C797S-Mediated Resistance

Yasheng Zhu1,2,3, Xiuquan Ye1,4, Hao Shen1,2,3

  • 1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Journal of Medicinal Chemistry
|October 27, 2023
PubMed

Insights

A new thiazole derivative, compound C34, effectively targets the C797S mutation in epidermal growth factor receptor (EGFR), overcoming Osimertinib resistance in non-small cell lung cancer (NSCLC). This discovery offers a promising therapeutic strategy for patients with resistant EGFR mutations.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Epidermal growth factor receptor (EGFR)-activating mutations drive non-small cell lung cancer (NSCLC).
  • Osimertinib is a first-line treatment for EGFR-mutated NSCLC, but resistance emerges due to the C797S mutation.
  • No approved inhibitors currently exist to combat Osimertinib resistance caused by the C797S mutation.

Purpose of the Study:

  • To identify novel inhibitors targeting the EGFR L858R/T790M/C797S triple mutation.
  • To develop a new therapeutic strategy to overcome Osimertinib resistance in NSCLC.

Main Methods:

  • Structure-based virtual screening was employed to identify a lead compound (S8).
  • A series of novel thiazole derivatives were synthesized.
  • In vitro and in vivo assays were conducted to evaluate the efficacy and pharmacokinetic properties of the lead compound (C34).

Main Results:

  • Compound C34 exhibited potent inhibitory activity against EGFR L858R/T790M/C797S (IC50 = 5.1 nM).
  • C34 significantly inhibited the proliferation of H1975-TM cells (IC50 = 0.05 μM) harboring the target mutation.
  • Compound C34 demonstrated favorable oral bioavailability (30.72%) and suppressed tumor growth in a xenograft model.

Conclusions:

  • A novel thiazole derivative, C34, effectively targets EGFR with the C797S resistance mutation.
  • C34 shows potential as a therapeutic agent to overcome Osimertinib resistance in NSCLC.
  • This study provides a promising new class of EGFR inhibitors for clinical development.

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