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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2024-05, Vol.67 (11), p.8988-9027
Main Authors: Thomson, Clare, Barton, Peter, Braybrooke, Erin, Colclough, Nicola, Dong, Zhiqiang, Evans, Laura, Floc’h, Nicolas, Guérot, Carine, Hargreaves, David, Khurana, Puneet, Li, Songlei, Li, Xiuwei, Lister, Andrew, McCoull, William, McWilliams, Lisa, Orme, Jonathan P., Packer, Martin J., Swaih, Aisha M., Ward, Richard A., Winlow, Poppy, Ye, Yang
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00227