Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations PMID: 38770784

ADC Targets in Oncology

2026-04-10

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

J Med Chem. 2024 Jun 13;67(11):8988-9027. doi: 10.1021/acs.jmedchem.4c00227.

Clare Thomson ¹ , Peter Barton ¹ , Erin Braybrooke ¹ , Nicola Colclough ¹ , Zhiqiang Dong ² , Laura Evans ¹ , Nicolas Floc'h ¹ , Carine Guérot ¹ , David Hargreaves ¹ , Puneet Khurana ¹ , Songlei Li ² , Xiuwei Li ² , Andrew Lister ¹ , William McCoull ¹ , Lisa McWilliams ¹ , Jonathan P Orme ¹ , Martin J Packer ¹ , Aisha M Swaih ¹ , Richard A Ward ¹ , Poppy Winlow ¹ , Yang Ye ²

Affiliations

Abstract

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.