Discovery of Nanomolar DCAF1 Small Molecule Ligands
DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 7 vom: 13. Apr., Seite 5041-5060 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
Carrier Proteins |
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| Anmerkungen: |
Date Completed 14.04.2023 Date Revised 07.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c02132 |
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| Förderinstitution / Projekttitel: |
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NLM354534262 |
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| 100 | 1 | |a Li, Alice Shi Ming |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of Nanomolar DCAF1 Small Molecule Ligands |
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| 500 | |a Date Revised 07.06.2023 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Kimani, Serah |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Noureldin, Mahmoud |e verfasserin |4 aut | |
| 700 | 1 | |a González-Álvarez, Héctor |e verfasserin |4 aut | |
| 700 | 1 | |a Mamai, Ahmed |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffer, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Guilinger, John P |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a von Rechenberg, Moritz |e verfasserin |4 aut | |
| 700 | 1 | |a Disch, Jeremy S |e verfasserin |4 aut | |
| 700 | 1 | |a Mulhern, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Slakman, Belinda L |e verfasserin |4 aut | |
| 700 | 1 | |a Cuozzo, John W |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Aiping |e verfasserin |4 aut | |
| 700 | 1 | |a Poda, Gennady |e verfasserin |4 aut | |
| 700 | 1 | |a Mohammed, Mohammed |e verfasserin |4 aut | |
| 700 | 1 | |a Saraon, Punit |e verfasserin |4 aut | |
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| 700 | 1 | |a Modh, Pratik |e verfasserin |4 aut | |
| 700 | 1 | |a Rathod, Vaibhavi |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Bhashant |e verfasserin |4 aut | |
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| 700 | 1 | |a Szewczyk, Magdalena M |e verfasserin |4 aut | |
| 700 | 1 | |a Barsyte-Lovejoy, Dalia |e verfasserin |4 aut | |
| 700 | 1 | |a Arrowsmith, Cheryl H |e verfasserin |4 aut | |
| 700 | 1 | |a Marcellus, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Guié, Marie-Aude |e verfasserin |4 aut | |
| 700 | 1 | |a Keefe, Anthony D |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Halabelian, Levon |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Awar, Rima |e verfasserin |4 aut | |
| 700 | 1 | |a Vedadi, Masoud |e verfasserin |4 aut | |
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