Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

Cell Reports
Krisna C Duong-LyJeffrey R Peterson

Abstract

Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases, including ALK, LRRK2, RET, and EGFR, as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.

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Citations

Apr 25, 2017·Scientific Reports·Francisco Martínez-JiménezMarc A Marti-Renom
May 26, 2017·ChemMedChem·Frieda A SorgenfreiBenjamin Merget
Jun 24, 2017·ChemMedChem·Luca MologniGiovanni Marzaro
Apr 1, 2019·Inflammopharmacology·Anja DulliusMárcia Inês Goettert
Sep 3, 2020·Nature Communications·Xiomaris M Cotto-RiosEvripidis Gavathiotis
Feb 19, 2020·Scientific Reports·Albert A AntolinBissan Al-Lazikani
Jun 24, 2016·Expert Review of Proteomics·Lois M Mulligan
Jun 13, 2020·The European Respiratory Journal·Jason WeatheraldDavid Montani
Jul 29, 2017·Molecular Cancer Therapeutics·Miho J FuseRyohei Katayama
Jul 1, 2021·British Journal of Clinical Pharmacology·Saiful IslamRichard Head
Oct 30, 2020·Journal of Chemical Information and Modeling·Steven K AlbaneseLingle Wang
Dec 26, 2018·Journal of Chemical Information and Modeling·Zheng ZhaoPhilip E Bourne
May 11, 2018·Journal of Medicinal Chemistry·Samo TurkSimone Fulle

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