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

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

  • Bioorg Med Chem. 2023 Nov 10:96:117534. doi: 10.1016/j.bmc.2023.117534.
Mengmeng Fan 1,  Liping Hu 1,  Shengmin Shi 1,  Xiaomeng Song 1,  Huan He 2,  Baohui Qi 3
Affiliations

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 EGFRL858R/T790M/C797S and EGFRDel19/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.

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