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Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells

G. Picco,Yanhua Rao,Angham Al Saedi,Yang Lee,Sara F. Vieira,S. Bhosle,Kieron May,Carmen Herranz-Ors,Samantha J. Walker,Ray Shenje,Cansu Dinçer,Freddy Gibson,Ruby Banerjee,Zoe Hewitson,Thilo Werner,Josh Cottom,Yang Peng,Nanhua Deng,Youyou Zhang,Eldridge N. Nartey,Leng Nickels,Phil Landis,Daniela Conticelli,Katrina McCarten,Jacob Bush,Mamta Sharma,H. Lightfoot,David House,E. Milford,Emma K. Grant,Michal P Glogowski,C. Wagner,M. Bantscheff,Anna Rutkowska-Klute,Francesca Zappacosta,Jonathan Pettinger,S. Barthorpe,H. Eberl,Brian T. Jones,Jess Schneck,Dennis J. Murphy,E. Voest,J. Taygerly,Michael P. DeMartino,M. Coelho,J. Houseley,Geeta Sharma,Benjamin Schwartz,Mathew J. Garnett

Published 2024 in Cancer Discovery

ABSTRACT

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.

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