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

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.
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

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 EGFRL858R/T790M/C797S. The representative compound C6 exhibited a DC50 of 10.2 nM against EGFRL858R/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 EGFRDel19/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.

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