7KBG

Structure of Human HDAC2 in complex with a 2-substituted benzamide inhibitor (compound 20)

Summary for 7KBG

• Entry DOI: 10.2210/pdb7kbg/pdb
• Descriptor: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (9 entities in total)
• Functional Keywords: histone deacetylase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 133318.19

Authors

Klein, D.J.,Liu, J. (deposition date: 2020-10-02, release date: 2020-12-30, Last modification date: 2024-03-06)

Primary citation

Liu, J.,Yu, Y.,Kelly, J.,Sha, D.,Alhassan, A.B.,Yu, W.,Maletic, M.M.,Duffy, J.L.,Klein, D.J.,Holloway, M.K.,Carroll, S.,Howell, B.J.,Barnard, R.J.O.,Wolkenberg, S.,Kozlowski, J.A.
Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.
Acs Med.Chem.Lett., 11:2476-2483, 2020

PubMed Abstract: The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound with a 2-methylthiobenzamide. Compound inhibited HDAC3 with an IC of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis and bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.

PubMed: 33335670
DOI: 10.1021/acsmedchemlett.0c00462

Experimental method

X-RAY DIFFRACTION (1.26 Å)