2. Academic Validation
  3. Discovery of Novel Fourth-Generation EGFR Inhibitors to Overcome C797S-Mediated Resistance

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

  • J Med Chem. 2023 Nov 9;66(21):14633-14652. doi: 10.1021/acs.jmedchem.3c01165.
Yasheng Zhu 1 2 3,  Xiuquan Ye 1 4,  Hao Shen 1 2 3,  Jiaxing Li 1 2 3,  Zeyu Cai 1 2 3,  Wenjian Min 1 2 3,  Yi Hou 1 2 3,  Haojie Dong 1 2 3,  Yuxing Wu 1 4,  Liping Wang 1 2 3,  Xiao Wang 1 2 3,  Yibei Xiao 1 4 5,  Peng Yang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
PMID: 37885208 DOI: 10.1021/acs.jmedchem.3c01165
Abstract

Epidermal growth factor receptor (EGFR)-activating mutation is an important oncogenic driver of nonsmall cell lung Cancer (NSCLC) patients. Osimertinib has been the first-line treatment for EGFR-mutated NSCLC. However, the tertiary C797S mutation leads to Osimertinib resistance by blocking the covalent binding of Cys797 to Osimertinib. To date, there are no approved inhibitors for the treatment of Osimertinib resistance. Herein, we identified a novel lead compound S8 targeting EGFRL858R/T790M/C797S by structure-based virtual screening and synthesized a series of novel compounds. Representative compound C34 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 5.1 nM and significantly inhibited the proliferation of the H1975-TM cell line harboring EGFRL858R/T790M/C797S with an IC50 of 0.05 μM. Additionally, compound C34 demonstrated good pharmacokinetic properties with an oral bioavailability of 30.72% and significantly inhibited tumor growth in the H1975-TM xenograft tumor model. This study provides a novel thiazole derivative as an EGFR inhibitor to overcome C797S-mediated resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156457
    EGFR Inhibitor