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Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers | Nature
by
Stephane Ferretti, Jacques Hamon, Ruben de Kanter, Clemens Scheufler, Rita Andraos-Rey, Stephanie Barbe, Elisabeth Bechter, Jutta Blank, Bordas Vincent, Ernesta Dammassa, Andrea Decker, Noemi Di Nanni, Marion Dourdoigne, Elena Gavioli, Marc Hattenberger, Alisa Heuser, Christelle HEMMERLIN, Jürgen Hinrichs, Grainne Kerr, Laurent LABORDE, Isabel Jaco, Eloísa Jiménez Núñez, Hans-Joerg Martus, Cornelia Quadt, Markus Reschke, Vincent Romanet, Fanny Schaeffer, Joseph Schoepfer, Maxime Thomas-Schrapp, Ross Strang, Hans Voshol, Markus Wartmann, Sarah Welly, Frederic Zecri, Francesco Hofmann, Henrik Moebitz & Marta Cortes-Crosés-Cros
Abstract:
The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1,2,3,4,5,6. Despite advances in treatment with immune checkpoint inhibitors7,8,9,10, there is an unmet need in the treatment of MSI cancers11,12,13,14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
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