作者
Gabriele Picco,Yanhua Rao,Angham Al Saedi,Yang Lee,Sara F. Vieira,Shriram G. Bhosle,Kieron May,Carmen Herranz,Samantha J. Walker,Raynold Shenje,Cansu Dinçer,Freddy Gibson,Ruby Banerjee,Zoe Hewitson,Thilo Werner,Joshua E. Cottom,Yang Peng,Nanhua Deng,Patricia Landis,Daniela Conticelli,Katrina McCarten,Jacob T. Bush,Mamta Sharma,Howard Lightfoot,David House,Emma Milford,Emma K. Grant,Michal P. Glogowski,Craig D. Wagner,Marcus Bantscheff,Ania Rutkowska,Cell Model Network UK Group,Francesca Zappacosta,Jonathan Pettinger,Syd Barthorpe,H. Christian Eberl,Brian T. Jones,Jessica L. Schneck,Dennis M. Murphy,Emile E. Voest,Joshua P. Taygerly,Michael P. DeMartino,Matthew A. Coelho,Jonathan Houseley,Geeta Sharma,Benjamin Schwartz,Mathew J. Garnett
摘要
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.