Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL–ML Hit
Herein we present the rapid development of LH168, a potent and highly selective chemical probe for WDR5, streamlined by utilizing a DEL-ML (DNA encoded library-machine learning) hit as the chemical starting point. LH168 was comprehensively characterized in bioassays and demonstrated potent <i>in cellulo</i> target engagement at the WIN-site pocket of WDR5, with an EC<sub>50</sub> of approximately 10 nM, a long residence time, and exceptional proteome-wide selectivity for WDR5. In addition, we present the X-ray co-crystal structure and provide insights into the structure-activity relationships (SAR). In parallel, we developed a matched negative control compound as well as an alkyne analog (compound 16) to facilitate the development of bifunctional molecules. Taken together, we provide the scientific community with a well-characterized chemical probe to enable studies and functional manipulation of WDR5 in a cellular context, as this protein represents a therapeutically relevant target with scaffolding functions that influence multiple cellular processes.
Authors
- H. Holzmann
- Matthias Gstaiger (ORCID: https://orcid.org/0000-0002-3245-3253)
- Serah Kimani (ORCID: https://orcid.org/0000-0002-6960-3833)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Sabrina Keller (ORCID: https://orcid.org/0000-0002-8976-9208)
- Irene Chau (ORCID: https://orcid.org/0000-0002-2313-973X)
- Christopher Lenz (ORCID: https://orcid.org/0009-0000-2261-2823)
- Václav Němec (ORCID: https://orcid.org/0000-0001-6900-1368)
- Martin P. Schwalm (ORCID: https://orcid.org/0000-0002-1252-1829)
- Susanne Müller (ORCID: https://orcid.org/0000-0003-2402-4157)
- Frederic Farges (ORCID: https://orcid.org/0009-0002-1531-8401)
- Lasse Hoffmann
- Andreas Krämer (ORCID: https://orcid.org/0000-0003-3294-2660)
- Johannes Dopfer (ORCID: https://orcid.org/0009-0008-6356-1864)
- Fengling Li (ORCID: https://orcid.org/0000-0001-9530-2068)
- A. Dong (ORCID: https://orcid.org/0000-0002-4444-4012)
- Levon Halebelian (ORCID: https://orcid.org/0000-0003-4361-3619)
Institutions
- Goethe University Frankfurt (DE)
- University Health Network (CA)
- German Cancer Research Center (DE)
- University of Toronto (CA)
- Heidelberg University (DE)
- Princess Margaret Cancer Centre (CA)
- Structural Genomics Consortium (CA)
- The Geneva Association (CH)
Publication Details
- Journal
- RSC Chemical Biology
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5cb00109a
- Citations
- 3
- Primary Topic
- Nuclear Physics and Applications
- Type
- article
- Field-Weighted Citation Impact
- 5.65
Funders
- Bristol-Myers Squibb
- Bayer
- Canadian Light Source
- McGill University
- Genome Canada
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Ontario Genomics Institute
- Mitacs
- Genentech
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada