WRN structural flexibility showcased through fragment-based lead discovery of inhibitors
WRN helicase is an established synthetic lethal target for inhibition in the treatment of microsatellite instability-high (MSI-H) and mismatch repair deficient (MMRd) cancers. The identification of helicase inhibitors is challenging as high-throughput biochemical screening campaigns typically return few validated hits that are often inactive in cell-based assays. Herein, we highlight the power of non-covalent fragment-based lead discovery in locating new druggable allosteric sites on WRN, enabling us to bypass the challenging behavior of WRN during high-throughput screening hampering hit identification. During the fragment optimization process, structures of WRN with key prioritized fragments reveal multiple conformations of WRN with significant domain rotations up to 180°, including a WRN conformation not previously described. Rooted in a combination of biochemical, biophysical, and structural approaches, we present the detailed analyses of optimized chemical matter evolved from screening hits and the unique ability of WRN to accommodate diverse conformations as detailed by structural characterization.
Authors
- R.L. Palte (ORCID: https://orcid.org/0000-0001-6146-0551)
- M.J. Tauchert
- Justyna Sikorska (ORCID: https://orcid.org/0000-0002-3836-6708)
- Robert J. Bauer (ORCID: https://orcid.org/0000-0001-6317-6933)
- Minjia Zhang (ORCID: https://orcid.org/0009-0005-1476-783X)
- Jacqueline D. Hicks
- Sriram Tyagarajan (ORCID: https://orcid.org/0000-0002-1123-7199)
- Jaclyn Robustelli
- Joey L. Methot (ORCID: https://orcid.org/0000-0003-3374-181X)
- Artjohn Villafania
- Daniel J. Klein (ORCID: https://orcid.org/0000-0002-3533-3273)
- Markus Koglin
- K. Maskos
- Mihir Mandal (ORCID: https://orcid.org/0000-0002-7870-7271)
- Sandra B. Gabelli (ORCID: https://orcid.org/0000-0003-1205-5204)
- Xiaomei Chai
- Meredith M. Rickard (ORCID: https://orcid.org/0000-0002-4571-9743)
- My Sam Mansueto (ORCID: https://orcid.org/0000-0001-8633-2556)
- Alexei V. Buevich (ORCID: https://orcid.org/0000-0002-5968-9151)
- Zahid Hussain (ORCID: https://orcid.org/0000-0002-6978-3133)
- Daniel F. Wyss (ORCID: https://orcid.org/0000-0002-5005-6104)
- Aileen Soriano
- David G. McLaren
- Jiafang He
- Hannah B. MacDonald
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- United States Military Academy (US)
- ProterixBio (United States) (US)
- Quantitative BioSciences (US)
- Molecular Discovery (United Kingdom) (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-03
- DOI
- https://doi.org/10.1038/s41467-025-66768-8
- Citations
- 1
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 22.24
Funders
- Diamond Light Source
- European Synchrotron Radiation Facility
- Paul Scherrer Institut