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

Yasheng Zhu; Xiuquan Ye; Hao Shen; Jiaxing Li; Zeyu Cai; Wenjian Min; Yi Hou; Haojie Dong; Yuxing Wu; Liping Wang; Xiao Wang; Yibei Xiao; Peng Yang

doi:10.1021/acs.jmedchem.3c01165

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. Epub 2023 Oct 27.

Authors

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

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 EGFR^{L858R/T790M/C797S} by structure-based virtual screening and synthesized a series of novel compounds. Representative compound C34 showed potent inhibitory activity against EGFR^{L858R/T790M/C797S} with an IC₅₀ of 5.1 nM and significantly inhibited the proliferation of the H1975-TM cell line harboring EGFR^{L858R/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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / pharmacology
Carcinoma, Non-Small-Cell Lung* / genetics
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors / metabolism
Humans
Lung Neoplasms* / metabolism
Mutation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use

Substances

osimertinib
ErbB Receptors
Protein Kinase Inhibitors
Aniline Compounds
EGFR protein, human