2. Academic Validation
  3. Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

  • J Med Chem. 2023 Sep 14;66(17):11656-11671. doi: 10.1021/acs.jmedchem.3c00875.
Hao Chen 1,  Shiliang Hu 1,  Adam V Patterson 2 3,  Jeff B Smaill 2 3,  Ke Ding 1 4,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 3 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 4 State Key Laboratory of Bioorganic and Nature Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
PMID: 37669428 DOI: 10.1021/acs.jmedchem.3c00875
Abstract

Epidermal growth factor receptor (EGFR) targeted therapy is one of the most important and effective strategies to combat EGFR mutant nonsmall-cell lung Cancer (NSCLC). However, a substantial number of patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond poorly to common EGFR targeted therapies. This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA. Despite this progress, the structural mechanisms of EGFR Ex20ins mutation resistance and characterization of inhibitor binding modes have not been systematically summarized. Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

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