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

Haojie Dong; Xiuquan Ye; Yasheng Zhu; Hao Shen; Hongtao Shen; Weijiao Chen; Minghui Ji; Mingming Zheng; Keren Wang; Zeyu Cai; Haopeng Sun; Yibei Xiao; Peng Yang

doi:10.1021/acs.jmedchem.3c00277

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. Epub 2023 May 4.

Authors

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

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 EGFR^{L858R/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 EGFR^{del19/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.

Publication types

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

MeSH terms

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

Substances

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