Q1 · MEDICINE
Article
Author: Dong, Aiping ; Li, Alice Shi Ming ; Saraon, Punit ; Wilson, Brian ; Guié, Marie-Aude ; Vedadi, Masoud ; Zhang, Ying ; Santhakumar, Vijayaratnam ; González-Álvarez, Héctor ; von Rechenberg, Moritz ; Modh, Pratik ; Arrowsmith, Cheryl H ; Mamai, Ahmed ; Mittal, Manish ; Brown, Peter J ; Mulhern, Christopher J ; Szewczyk, Magdalena M ; Patel, Bhashant ; Al-Awar, Rima ; Mohammed, Mohammed ; Noureldin, Mahmoud ; Halabelian, Levon ; Disch, Jeremy S ; Kimani, Serah ; Slakman, Belinda L ; Hoffer, Laurent ; Barsyte-Lovejoy, Dalia ; Keefe, Anthony D ; Rathod, Vaibhavi ; Marcellus, Richard ; Cuozzo, John W ; Ackloo, Suzanne ; Poda, Gennady ; Guilinger, John P
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.