Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites

Mengmeng Fan; Liping Hu; Shengmin Shi; Xiaomeng Song; Huan He; Baohui Qi

doi:10.1016/j.bmc.2023.117534

Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites

Bioorg Med Chem. 2023 Dec 15:96:117534. doi: 10.1016/j.bmc.2023.117534. Epub 2023 Nov 10.

Authors

Mengmeng Fan¹, Liping Hu¹, Shengmin Shi¹, Xiaomeng Song¹, Huan He², Baohui Qi³

Affiliations

¹ School of Bioengineering, Zunyi Medical University, Zhuhai 519041, China; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, Zunyi 563000, China.
² School of Bioengineering, Zunyi Medical University, Zhuhai 519041, China. Electronic address: bhqi@zmu.gd.cn.
³ School of Bioengineering, Zunyi Medical University, Zhuhai 519041, China; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, Zunyi 563000, China. Electronic address: bhqi@zmu.gd.cn.

PMID: 37952262
DOI: 10.1016/j.bmc.2023.117534

Abstract

Acquired drug resistance occurred in the treatment of non-small-cell lung cancer is a persistent challenge, especially in EGFR mutant type. In this study, we present design, synthesis and biological evaluation of novel quinazoline and pyrrolopyrimidine derivatives that simultaneously occupy the orthosteric and allosteric sites of EGFR. Among them, compound A-7 was confirmed as a potential EGFR^{L858R/T790M/C797S} and EGFR^{Del19/T790M/C797S} inhibitor. Docking study indicated that compound A-7 could simultaneously occupy two binding sites of EGFR and form three key H-bonds with the residues Met793, Lys745 and Met766 in two regions.

Keywords: Allosteric inhibitors; Anticancer; EGFR; Quinazoline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Carcinoma, Non-Small-Cell Lung* / drug therapy
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Lung Neoplasms* / drug therapy
Mutation
Protein Kinase Inhibitors / chemistry

Substances

ErbB Receptors
A 7
Protein Kinase Inhibitors
EGFR protein, human