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000304501 1001_ $$aHoffmann, Lasse$$b0
000304501 245__ $$aDiscovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL-ML Hit.
000304501 260__ $$aCambridge$$bThe Royal Society of Chemistry$$c2025
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000304501 520__ $$aHerein we present the rapid development of LH168, a potent and highly selective chemical probe for WDR5, streamlined by utilizing a DEL-ML (DNA encoded library-machine learning) hit as the chemical starting point. LH168 was comprehensively characterized in bioassays and demonstrated potent in cellulo target engagement at the WIN-site pocket of WDR5, with an EC50 of approximately 10 nM, a long residence time, and exceptional proteome-wide selectivity for WDR5. In addition, we present the X-ray co-crystal structure and provide insights into the structure-activity relationships (SAR). In parallel, we developed a matched negative control compound as well as an alkyne analog (compound 16) to facilitate the development of bifunctional molecules. Taken together, we provide the scientific community with a well-characterized chemical probe to enable studies and functional manipulation of WDR5 in a cellular context, as this protein represents a therapeutically relevant target with scaffolding functions that influence multiple cellular processes.
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000304501 7001_ $$00009-0000-2261-2823$$aLenz, Christopher$$b1
000304501 7001_ $$aFarges, Frederic$$b2
000304501 7001_ $$00000-0002-6960-3833$$aKimani, Serah W$$b3
000304501 7001_ $$aDopfer, Johannes$$b4
000304501 7001_ $$00000-0002-8976-9208$$aKeller, Sabrina$$b5
000304501 7001_ $$00000-0002-1252-1829$$aSchwalm, Martin Peter$$b6
000304501 7001_ $$aHolzmann, Hanna$$b7
000304501 7001_ $$aKraemer, Andreas$$b8
000304501 7001_ $$aDong, Aiping$$b9
000304501 7001_ $$aLi, Fengling$$b10
000304501 7001_ $$aChau, Irene$$b11
000304501 7001_ $$00000-0003-4361-3619$$aHalabelian, Levon$$b12
000304501 7001_ $$00000-0002-3245-3253$$aGstaiger, Matthias$$b13
000304501 7001_ $$00000-0003-2402-4157$$aMüller, Susanne$$b14
000304501 7001_ $$00000-0001-5995-6494$$aKnapp, Stefan$$b15
000304501 7001_ $$00000-0001-6900-1368$$aNěmec, Václav$$b16
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