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Discovery of Nanomolar DCAF1 Small Molecule Ligands.


ABSTRACT: 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.

SUBMITTER: Li ASM 

PROVIDER: S-EPMC10108359 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Discovery of Nanomolar DCAF1 Small Molecule Ligands.

Li Alice Shi Ming ASM   Kimani Serah S   Wilson Brian B   Noureldin Mahmoud M   González-Álvarez Héctor H   Mamai Ahmed A   Hoffer Laurent L   Guilinger John P JP   Zhang Ying Y   von Rechenberg Moritz M   Disch Jeremy S JS   Mulhern Christopher J CJ   Slakman Belinda L BL   Cuozzo John W JW   Dong Aiping A   Poda Gennady G   Mohammed Mohammed M   Saraon Punit P   Mittal Manish M   Modh Pratik P   Rathod Vaibhavi V   Patel Bhashant B   Ackloo Suzanne S   Santhakumar Vijayaratnam V   Szewczyk Magdalena M MM   Barsyte-Lovejoy Dalia D   Arrowsmith Cheryl H CH   Marcellus Richard R   Guié Marie-Aude MA   Keefe Anthony D AD   Brown Peter J PJ   Halabelian Levon L   Al-Awar Rima R   Vedadi Masoud M  

Journal of medicinal chemistry 20230322 7


DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4<sup>DCAF1</sup> 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 d  ...[more]

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