2. Academic Validation
  3. Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

  • J Med Chem. 2023 May 25;66(10):6849-6868. doi: 10.1021/acs.jmedchem.3c00277.
Haojie Dong 1 2 3,  Xiuquan Ye 1 4,  Yasheng Zhu 1 2 3,  Hao Shen 1 2 3,  Hongtao Shen 1 4,  Weijiao Chen 1 2 3,  Minghui Ji 1 2 3,  Mingming Zheng 1 2 3,  Keren Wang 1 4,  Zeyu Cai 1 2 3,  Haopeng Sun 1 2,  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: 37141440 DOI: 10.1021/acs.jmedchem.3c00277
Abstract

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung Cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

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