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| Home > Publications database > Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL-ML Hit. > print |
| 001 | 304501 | ||
| 005 | 20250914022658.0 | ||
| 024 | 7 | _ | |a 10.1039/D5CB00109A |2 doi |
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| 037 | _ | _ | |a DKFZ-2025-01890 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 540 |
| 100 | 1 | _ | |a Hoffmann, Lasse |b 0 |
| 245 | _ | _ | |a Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL-ML Hit. |
| 260 | _ | _ | |a Cambridge |c 2025 |b The Royal Society of Chemistry |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1757580747_26503 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a epub |
| 520 | _ | _ | |a 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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| 700 | 1 | _ | |a Lenz, Christopher |0 0009-0000-2261-2823 |b 1 |
| 700 | 1 | _ | |a Farges, Frederic |b 2 |
| 700 | 1 | _ | |a Kimani, Serah W |0 0000-0002-6960-3833 |b 3 |
| 700 | 1 | _ | |a Dopfer, Johannes |b 4 |
| 700 | 1 | _ | |a Keller, Sabrina |0 0000-0002-8976-9208 |b 5 |
| 700 | 1 | _ | |a Schwalm, Martin Peter |0 0000-0002-1252-1829 |b 6 |
| 700 | 1 | _ | |a Holzmann, Hanna |b 7 |
| 700 | 1 | _ | |a Kraemer, Andreas |b 8 |
| 700 | 1 | _ | |a Dong, Aiping |b 9 |
| 700 | 1 | _ | |a Li, Fengling |b 10 |
| 700 | 1 | _ | |a Chau, Irene |b 11 |
| 700 | 1 | _ | |a Halabelian, Levon |0 0000-0003-4361-3619 |b 12 |
| 700 | 1 | _ | |a Gstaiger, Matthias |0 0000-0002-3245-3253 |b 13 |
| 700 | 1 | _ | |a Müller, Susanne |0 0000-0003-2402-4157 |b 14 |
| 700 | 1 | _ | |a Knapp, Stefan |0 0000-0001-5995-6494 |b 15 |
| 700 | 1 | _ | |a Němec, Václav |0 0000-0001-6900-1368 |b 16 |
| 773 | _ | _ | |a 10.1039/D5CB00109A |g p. 10.1039.D5CB00109A |0 PERI:(DE-600)3037398-0 |p nn |t RSC chemical biology |v nn |y 2025 |x 2633-0679 |
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