8G43

Structure of HDAC6 zinc-finger ubiquitin binding domain in complex with 3-(3-(2-(methylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propanoic acid

Summary for 8G43

• Entry DOI: 10.2210/pdb8g43/pdb
• Descriptor: Histone deacetylase 6, ZINC ION, 3-{3-[2-(methylamino)-2-oxoethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}propanoic acid, ... (4 entities in total)
• Functional Keywords: inhibitor, chemical probe, hdac6, histone deacetylase, structural genomics, structural genomics consortium, sgc, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12418.12

Authors

Harding, R.J.,Franzoni, I.,Mann, M.K.,Szewczyk, M.,Mirabi, B.,Owens, D.D.G.,Ackloo, S.,Scheremetjew, A.,Juarez-Ornelas, K.A.,Sanichar, R.,Baker, R.J.,Dank, C.,Brown, P.J.,Barsyte-Lovejoy, D.,Santhakumar, V.,Schapira, M.,Lautens, M.,Arrowsmith, C.H.,Structural Genomics Consortium (SGC) (deposition date: 2023-02-08, release date: 2023-05-03, Last modification date: 2023-08-16)

Primary citation

Harding, R.J.,Franzoni, I.,Mann, M.K.,Szewczyk, M.M.,Mirabi, B.,Ferreira de Freitas, R.,Owens, D.D.G.,Ackloo, S.,Scheremetjew, A.,Juarez-Ornelas, K.A.,Sanichar, R.,Baker, R.J.,Dank, C.,Brown, P.J.,Barsyte-Lovejoy, D.,Santhakumar, V.,Schapira, M.,Lautens, M.,Arrowsmith, C.H.
Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6.
J.Med.Chem., 66:10273-10288, 2023

PubMed Abstract: Histone deacetylase 6 (HDAC6) inhibition is an attractive strategy for treating numerous cancers, and HDAC6 catalytic inhibitors are currently in clinical trials. The HDAC6 zinc-finger ubiquitin-binding domain (UBD) binds free C-terminal diglycine motifs of unanchored ubiquitin polymer chains and protein aggregates, playing an important role in autophagy and aggresome assembly. However, targeting this domain with small molecule antagonists remains an underdeveloped avenue of HDAC6-focused drug discovery. We report (), a chemical probe potently targeting HDAC6-UBD in vitro with selectivity over nine other UBDs, except for weak USP16 binding. In cells, is an effective antagonist of HDAC6-UBD at 1 μM, with marked proteome-wide selectivity. We identified (), a methylated derivative of that is 300-fold less active, serving as a negative control. Together, and could enable further exploration of the biological function of the HDAC6-UBD and investigation of the therapeutic potential of targeting this domain.

PubMed: 37499118
DOI: 10.1021/acs.jmedchem.3c00314

Experimental method

X-RAY DIFFRACTION (1.55 Å)