Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines

  • Bioorg Med Chem Lett. 2024 Sep 14:113:129961. doi: 10.1016/j.bmcl.2024.129961.
Liang-Liang Guo  1 ,  Yan-Hong Zhang  2 ,  Jun-Fang Zuo  1 ,  Yi Cheng  1 ,  Guoliang Chen  3 ,  Chao Li  4
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China.
  • 3. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].
PMID: 39278366 DOI: 10.1016/j.bmcl.2024.129961
Abstract

The EGFR-TK pathway is pivotal in non-small-cell lung Cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.

Keywords
4th-gen EGFR TKIs; ATP depletion; C797S mutation; NSCLC; Polyamines; Quinazoline derivatives.
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