Structure-based rational design and biological evaluation of a quinazoline-based EGFR exon 20 insertion inhibitor.

Authors

Sooheum Jo, Hyunsoo Jang, Suin Kim, Jaebong Jang

Published in

Journal of enzyme inhibition and medicinal chemistry. Volume 41. Issue 1. Pages 2730846. Epub Sep 25, 2026.

Abstract

This study describes the structure-based design and synthesis of potent quinazoline-based inhibitors targeting EGFR exon 20 insertion (exon20ins) mutants, one of the challenging oncogenic drivers in non-small cell lung cancer (NSCLC). Guided by in silico modelling, a novel series of quinazoline analogues was designed to incorporate an intramolecular hydrogen bond between the hinge-binding motif and a substituent introduced at the 5-position via an ether linkage. This strategy was hypothesised to pre-organise the inhibitor conformation and improve biochemical inhibitory potency. We synthesised and evaluated 36 compounds, identifying key structure-activity relationships. Notably, we found that the R-configuration of 1-(2-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one at the 5-position and specific aniline types at the 4-position of quinazoline significantly improved inhibitory activity against EGFR exon20ins in biochemical kinase assays. The most potent analogues exhibited sub-nanomolar IC₅₀ values against various EGFR exon20ins mutants, and these findings could provide useful insights for the development of inhibitors targeting EGFR exon 20 insertions.

PMID:
42789311
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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