AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen.

Geoffrey M T Smith¹, Laksh Aithani², Charlotte E Barrett², Alwin O Bucher², Christopher D O Cooper², Sébastien L Degorce², Andrew S Doré², Catherine T Fletcher², Sophie Huber², Rosemary Huckvale², Amanda J Kennedy², Abigail A Mornement², Mark Pickworth², Prakash Rucktooa², Conor C G Scully², Sarah E Skerratt²

¹CHARM Therapeutics Ltd., B900, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, UK.. Electronic address: geoffrey@charmtx.com.

²CHARM Therapeutics Ltd., B900, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, UK.

PubMed DOI

Abstract

Werner (WRN) helicase, has emerged as a promising therapeutic target for cancers associated with microsatellite instability (MSI). This letter describes the discovery of small molecule inhibitors from a fragment screen that occupy a cryptic, allosteric site of WRN helicase. Key findings include the identification of benzimidazole and amino-indazole scaffolds, exploiting their proximity to Cys727 v…

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