Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation

Yasheng Zhu; Xiuquan Ye; Yuxing Wu; Hao Shen; Zeyu Cai; Fei Xia; Wenjian Min; Yi Hou; Liping Wang; Xiao Wang; Yibei Xiao; Peng Yang

doi:10.1021/acs.jmedchem.4c00107

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation

J Med Chem. 2024 May 9;67(9):7283-7300. doi: 10.1021/acs.jmedchem.4c00107. Epub 2024 Apr 27.

Authors

Yasheng Zhu^{1

2

3}, Xiuquan Ye^{1

4}, Yuxing Wu^{1

4}, Hao Shen^{1

2

3}, Zeyu Cai^{1

2

3}, Fei Xia^{1

2

3}, Wenjian Min^{1

2

3}, Yi Hou^{1

2

3}, 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: 38676656
DOI: 10.1021/acs.jmedchem.4c00107

Abstract

The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application of Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy to overcome drug resistance. In this study, some novel PROTACs targeting C797S mutation were designed and synthesized based on a new EGFR inhibitor and displayed a potent degradation effect in H1975-TM cells harboring EGFR^{L858R/T790M/C797S}. The representative compound C6 exhibited a DC₅₀ of 10.2 nM against EGFR^{L858R/T790M/C797S} and an IC₅₀ of 10.3 nM against H1975-TM. Furthermore, C6 also showed potent degradation activity against various main EGFR mutants, including EGFR^{Del19/T790M/C797S}. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, C6 inhibited tumor growth in the H1975-TM xenograft tumor model effectively and safely. This study identifies a novel and potent EGFR PROTAC to overcome Osimertinib resistance mediated by C797S mutation.

Publication types

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

MeSH terms

Acrylamides / chemical synthesis
Acrylamides / chemistry
Acrylamides / pharmacology
Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / pharmacology
Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Drug Resistance, Neoplasm / drug effects
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / genetics
ErbB Receptors* / metabolism
Humans
Indoles
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation*
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Proteolysis Targeting Chimera
Proteolysis* / drug effects
Pyrimidines
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

ErbB Receptors
EGFR protein, human
Antineoplastic Agents
Protein Kinase Inhibitors
Acrylamides
osimertinib
Aniline Compounds
Proteolysis Targeting Chimera
Indoles
Pyrimidines