Alice Shi Ming Li; Serah Kimani; Brian Wilson; Mahmoud Noureldin; Héctor González-Álvarez; Ahmed Mamai; Laurent Hoffer; John P. Guilinger; Ying Zhang; Moritz von Rechenberg; Jeremy S. Disch; Christopher J. Mulhern; Belinda L. Slakman; John W. Cuozzo; Aiping Dong; Gennady Poda; Mohammed Mohammed; Punit Saraon; Manish Mittal; Pratik Modh; Vaibhavi Rathod; Bhashant Patel; Suzanne Ackloo; Vijayaratnam Santhakumar; Magdalena M. Szewczyk; Dalia Barsyte-Lovejoy; Cheryl H. Arrowsmith; Richard Marcellus; Marie-Aude Guié; Anthony D. Keefe; Peter J. Brown; Levon Halabelian; Rima Al-awar; Masoud Vedadi
J. Med. Chem., 2023, 66(7), 5041-5060
https://doi.org/10.1021/acs.jmedchem.2c02132

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.