Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

Stephane Ferretti, Jacques Hamon, Ruben Kanter, Clemens Scheufler, Rita Andraos-Rey, Stephanie Barbe, Elisabeth Bechter, Jutta Blank, Vincent Bordas, Ernesta Dammassa, Andrea Decker, Noemi 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 Schrapp, Ross Strang, Hans Voshol, Markus Wartmann, Sarah Welly, Frédéric Zécri, Francesco Hofmann, Henrik Möbitz () and Marta Cortés-Cros ()
Additional contact information
Stephane Ferretti: Novartis BioMedical Research
Jacques Hamon: Novartis BioMedical Research
Ruben Kanter: Novartis BioMedical Research
Clemens Scheufler: Novartis BioMedical Research
Rita Andraos-Rey: Novartis BioMedical Research
Stephanie Barbe: Novartis BioMedical Research
Elisabeth Bechter: Novartis BioMedical Research
Jutta Blank: Novartis BioMedical Research
Vincent Bordas: Novartis BioMedical Research
Ernesta Dammassa: Novartis BioMedical Research
Andrea Decker: Novartis BioMedical Research
Noemi Nanni: Novartis BioMedical Research
Marion Dourdoigne: Novartis BioMedical Research
Elena Gavioli: Novartis BioMedical Research
Marc Hattenberger: Novartis BioMedical Research
Alisa Heuser: Novartis BioMedical Research
Christelle Hemmerlin: Novartis BioMedical Research
Jürgen Hinrichs: Novartis BioMedical Research
Grainne Kerr: Novartis BioMedical Research
Laurent Laborde: Novartis BioMedical Research
Isabel Jaco: Novartis BioMedical Research
Eloísa Jiménez Núñez: Novartis BioMedical Research
Hans-Joerg Martus: Novartis BioMedical Research
Cornelia Quadt: Novartis BioMedical Research
Markus Reschke: Novartis BioMedical Research
Vincent Romanet: Novartis BioMedical Research
Fanny Schaeffer: Novartis BioMedical Research
Joseph Schoepfer: Novartis BioMedical Research
Maxime Schrapp: Novartis BioMedical Research
Ross Strang: Novartis BioMedical Research
Hans Voshol: Novartis BioMedical Research
Markus Wartmann: Novartis BioMedical Research
Sarah Welly: Novartis BioMedical Research
Frédéric Zécri: Novartis BioMedical Research
Francesco Hofmann: Novartis BioMedical Research
Henrik Möbitz: Novartis BioMedical Research
Marta Cortés-Cros: Novartis BioMedical Research

Nature, 2024, vol. 629, issue 8011, 443-449

Abstract: Abstract The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07350-y

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