8PFL

Crystal structure of WRN helicase domain in complex with 3

Summary for 8PFL

• Entry DOI: 10.2210/pdb8pfl/pdb
• Descriptor: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, ZINC ION, 2-[2-(3,6-dihydro-2~{H}-pyran-4-yl)-5-ethyl-7-oxidanylidene-6-[4-(3-oxidanylpyridin-2-yl)carbonylpiperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-~{N}-[2-methyl-4-(trifluoromethyl)phenyl]ethanamide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 49358.08

Authors

Scheufler, C.,Meyer, M.,Moebitz, H. (deposition date: 2023-06-16, release date: 2024-04-24, Last modification date: 2024-05-22)

Primary citation

Ferretti, S.,Hamon, J.,de Kanter, R.,Scheufler, C.,Andraos-Rey, R.,Barbe, S.,Bechter, E.,Blank, J.,Bordas, V.,Dammassa, E.,Decker, A.,Di Nanni, N.,Dourdoigne, M.,Gavioli, E.,Hattenberger, M.,Heuser, A.,Hemmerlin, C.,Hinrichs, J.,Kerr, G.,Laborde, L.,Jaco, I.,Nunez, E.J.,Martus, H.J.,Quadt, C.,Reschke, M.,Romanet, V.,Schaeffer, F.,Schoepfer, J.,Schrapp, M.,Strang, R.,Voshol, H.,Wartmann, M.,Welly, S.,Zecri, F.,Hofmann, F.,Mobitz, H.,Cortes-Cros, M.
Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.
Nature, 629:443-449, 2024

PubMed Abstract: The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens. Despite advances in treatment with immune checkpoint inhibitors, there is an unmet need in the treatment of MSI cancers. 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.

PubMed: 38658754
DOI: 10.1038/s41586-024-07350-y

Experimental method

X-RAY DIFFRACTION (1.8 Å)