9CBI

Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with p-Aminoethyl Phenylthioketone

This is a non-PDB format compatible entry.

Summary for 9CBI

• Entry DOI: 10.2210/pdb9cbi/pdb
• Descriptor: Polyamine deacetylase HDAC10, 1,2-ETHANEDIOL, 1-[4-(2-aminoethyl)phenyl]-2-sulfanylethan-1-one, ... (7 entities in total)
• Functional Keywords: hydrolase, histone deacetylase, inhibitor, metallohydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 1
• Total formula weight: 75832.74

Authors

Goulart Stollmaier, J.,Christianson, D.W. (deposition date: 2024-06-19, release date: 2024-09-11, Last modification date: 2024-10-30)

Primary citation

Goulart Stollmaier, J.,Watson, P.R.,Christianson, D.W.
Design, Synthesis, and Structural Evaluation of Acetylated Phenylthioketone Inhibitors of HDAC10.
Acs Med.Chem.Lett., 15:1715-1723, 2024

PubMed Abstract: Histone deacetylase 10 (HDAC10) is unique among the greater HDAC family due to its unusually narrow substrate specificity as a polyamine deacetylase, specifically as an -acetylspermidine hydrolase. Polyamines are essential for cell growth and proliferation; consequently, inhibition of polyamine deacetylation represents a possible strategy for cancer chemotherapy. In this work, we have designed six acetylated phenylthioketone inhibitors of HDAC10 containing positively charged - and -substituted amino groups designed to target interactions with E274, the gatekeeper that recognizes the positively charged ammonium group of the substrate -acetylspermidine. We prepared each of these inhibitors through a short synthetic route of six steps. By adapting a low-cost colorimetric activity assay, we measured low-micromolar IC values for these compounds against a humanized construct of zebrafish HDAC10 (A24E-D94A HDAC10). Selected inhibitors were cocrystallized with A24E-D94A zebrafish HDAC10 and zebrafish HDAC6 to provide insight into class IIb isozyme affinity and selectivity.

PubMed: 39411528
DOI: 10.1021/acsmedchemlett.4c00293

Experimental method

X-RAY DIFFRACTION (2.5 Å)