jm2c02132_si_002.csv (2.26 kB)
Discovery of Nanomolar DCAF1 Small Molecule Ligands
dataset
posted on 2023-03-23, 00:05 authored by 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 VedadiDCAF1 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.
