1. Academic Validation
  2. Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells

Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells

  • Cancer Discov. 2024 Apr 9. doi: 10.1158/2159-8290.CD-24-0052.
Gabriele Picco 1 Yanhua Rao 2 Angham Al Saedi 1 Yang Lee 2 Sara F Vieira 3 Shriram Bhosle 1 Kieron May 4 Carmen Herranz-Ors 1 Samantha J Walker 1 Raynold Shenje 2 Cansu Dincer 1 Freddy Gibson 1 Ruby Banerjee 5 Zoe Hewitson 1 Thilo Werner 6 Joshua E Cottom 7 Yang Peng 8 Nanhua Deng 9 Philip Landis 2 Daniela Conticelli 10 Katrina McCarten 11 Jacob Bush 12 Mamta Sharma 1 Howard Lightfoot 1 David House 12 Emma Milford 12 Emma K Grant 12 Michal P Glogowski 12 Craig D Wagner 2 Marcus Bantscheff 6 Anna Rutkowska-Klute 6 Cell Model Network Uk Group 1 Francesca Zappacosta 13 Jonathan Pettinger 12 Syd Barthorpe 14 H Christian Eberl 6 Brian T Jones 15 Jessica L Schneck 16 Dennis J Murphy 2 Emile E Voest 17 Joshua P Taygerly 15 Michael P DeMartino 2 Matthew A Coelho 1 Jonathan Houseley 4 Geeta Sharma 18 Benjamin J Schwartz 13 Mathew J Garnett 1
Affiliations

Affiliations

  • 1 Wellcome Sanger Institute, Cambridge, United Kingdom.
  • 2 GSK, Upper Providence, PA, US 19426, United States.
  • 3 AstraZeneca, United Kingdom.
  • 4 Babraham Institute, Cambridge, United Kingdom.
  • 5 Wellcome Sanger Institute, United Kingdom.
  • 6 Cellzome, a GSK company, Heidelberg, Germany.
  • 7 GlaxoSmithKline (United States), Upper Providence, PA, United States.
  • 8 The University of Texas MD Anderson Cancer Center, Houston, TEXAS, United States.
  • 9 GSK, Brookline, MA, United States.
  • 10 University of Torino, Candiolo Cancer Institute - FPO,IRCCS, Candiolo, TO, Italy.
  • 11 Wellcome Sanger Institute, Hinxton, United Kingdom.
  • 12 GSK, Stevenage, United Kingdom.
  • 13 GlaxoSmithKline (United States), Collegeville, PA, United States.
  • 14 Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
  • 15 Ideaya Biosciences (United States), United States.
  • 16 GSK, Upper Providence, PA, US 19426, Collegeville, United States.
  • 17 Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 18 GlaxoSmithKline (United States), United States.
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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