Cancers with microsatellite instability (MSI) are defined by the accumulation of insertion and/or deletion mutations in microsatellites due to loss of DNA mismatch repair activity. Synthetic lethal genetic screens previously identified a dependence of MSI on the Werner syndrome RecQ helicase WRN, which normally ensures the maintenance of genomic stability and DNA repair. Genetic inhibition of WRN in MSI cancers results in DNA damage, cell death and decreased tumor growth, suggesting a potential druggable target. Baltgalvis et al. have now used a mass spectrometry-based chemoproteomics approach to enable the identification of covalent, allosteric molecules that selectivity engage C727 on WRN and that were optimized to provide VVD-133214. In a second paper, Ferretti et al. developed an ATP-binding screen to identify a non-covalent inhibitor of WRN activity with medicinal chemistry optimization revealing HRO761 as the most active compound. Crystal structures of WRN in complex with the inhibitors showed binding at a non-conserved site at the interface of the D1/D2 helicase domain to trap WRN in an inactive conformation. HRO761 and VVD-133214 were selectively cytotoxic in MSI-H cells, inducing DNA damage and cell cycle arrest while sparing microsatellite-stable cancer cells. Both compounds exhibited good physicochemical, pharmacokinetic and target engagement properties and limited toxicity. Treatment with either inhibitor reduced MSI-H and patient-derived mouse xenograft tumor growth through increased DNA damage. The combination of HRO761 and irinotecan, an inhibitor of DNA topoisomerase I, exhibited enhanced effects in vitro and in vivo while VVD-133214 was active in MSI-H tumors that are immunotherapy resistant. Overall, the work from Baltgalvis et al. and Ferretti et al. revealed a potential therapeutic for MSI cancers.
Original references: Nature 629, 435–442 (2024); Nature 629, 443–449 (2024)
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