6XDM

STRUCTURE OF HUMAN HDAC2 IN COMPLEX WITH AN ARYL KETONE INHIBITOR

Summary for 6XDM

• Entry DOI: 10.2210/pdb6xdm/pdb
• Descriptor: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (7 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: 132740.70

Authors

Klein, D.J.,Liu, J. (deposition date: 2020-06-11, release date: 2020-07-29, Last modification date: 2024-03-06)

Primary citation

Liu, J.,Kelly, J.,Yu, W.,Clausen, D.,Yu, Y.,Kim, H.,Duffy, J.L.,Chung, C.C.,Myers, R.W.,Carroll, S.,Klein, D.J.,Fells, J.,Holloway, M.K.,Wu, J.,Wu, G.,Howell, B.J.,Barnard, R.J.O.,Kozlowski, J.A.
Selective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance.
Acs Med.Chem.Lett., 11:1476-1483, 2020

PubMed Abstract: HIV persistence in latently infected, resting CD4 T cells is broadly considered a barrier to eradicate HIV. Activation of the provirus using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs has been touted as a promising therapeutic approach. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. Several clinical HDAC inhibitors had been examined as LRAs, which induced HIV activation in vitro and in vivo. Here we report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells. The SAR led to the discovery of a highly selective class I HDAC inhibitor with excellent potency. HDACi induces the HIV P24 protein in patient latent CD4 T cells.

PubMed: 32676157
DOI: 10.1021/acsmedchemlett.0c00302

Experimental method

X-RAY DIFFRACTION (1.56 Å)