Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation

Bioorg Med Chem Lett. 2024 Jan 15:98:129575. doi: 10.1016/j.bmcl.2023.129575. Epub 2023 Dec 6.

Abstract

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.

Keywords: C797S; Drug discovery; EGFR.

MeSH terms

  • Drug Resistance, Neoplasm
  • ErbB Receptors* / drug effects
  • ErbB Receptors* / genetics
  • Humans
  • Lung Neoplasms* / genetics
  • Mutation
  • Niacinamide* / analogs & derivatives
  • Niacinamide* / chemistry
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Tyrosine Kinase Inhibitors* / chemistry
  • Tyrosine Kinase Inhibitors* / pharmacology

Substances

  • EGFR protein, human
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Tyrosine Kinase Inhibitors
  • Niacinamide