7UFV

Crystal structure of the WDR domain of human DCAF1 in complex with OICR-6766

Summary for 7UFV

• Entry DOI: 10.2210/pdb7ufv/pdb
• Descriptor: DDB1- and CUL4-associated factor 1, (3P)-N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-3-(2-fluorophenyl)-1H-pyrazole-4-carboxamide, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: wd-repeat, wdr, dcaf1, sgc, structural genomics, structural genomics consortium, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 72346.31

Authors

Kimani, S.,Li, A.,Li, Y.,Dong, A.,Hutchinson, A.,Seitova, A.,Wilson, B.,Al-Awar, R.,Vedadi, M.,Brown, P.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (deposition date: 2022-03-23, release date: 2022-05-04, Last modification date: 2024-04-03)

Primary citation

Li, A.S.M.,Kimani, S.,Wilson, B.,Noureldin, M.,Gonzalez-Alvarez, H.,Mamai, A.,Hoffer, L.,Guilinger, J.P.,Zhang, Y.,von Rechenberg, M.,Disch, J.S.,Mulhern, C.J.,Slakman, B.L.,Cuozzo, J.W.,Dong, A.,Poda, G.,Mohammed, M.,Saraon, P.,Mittal, M.,Modh, P.,Rathod, V.,Patel, B.,Ackloo, S.,Santhakumar, V.,Szewczyk, M.M.,Barsyte-Lovejoy, D.,Arrowsmith, C.H.,Marcellus, R.,Guie, M.A.,Keefe, A.D.,Brown, P.J.,Halabelian, L.,Al-Awar, R.,Vedadi, M.
Discovery of Nanomolar DCAF1 Small Molecule Ligands.
J.Med.Chem., 66:5041-5060, 2023

PubMed Abstract: DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4 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 of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 () with an SPR of 38 nM and cellular target engagement with EC 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.

PubMed: 36948210
DOI: 10.1021/acs.jmedchem.2c02132

Experimental method

X-RAY DIFFRACTION (1.9 Å)