2. Academic Validation
  3. Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines

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

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: spucgl@163.com.
  • 4 State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: lichao@mail.buct.edu.cn.
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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