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| Home > Publications database > Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL-ML Hit. |
| Journal Article | DKFZ-2025-01890 |
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2025
The Royal Society of Chemistry
Cambridge
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Please use a persistent id in citations: doi:10.1039/D5CB00109A
Abstract: 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 in cellulo target engagement at the WIN-site pocket of WDR5, with an EC50 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.
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