7LTG

STRUCTURE OF HUMAN HDAC2 IN COMPLEX WITH APICIDIN

Summary for 7LTG

• Entry DOI: 10.2210/pdb7ltg/pdb
• Descriptor: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (6 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: 132609.25

Authors

Klein, D.J.,Beshore, D.C. (deposition date: 2021-02-19, release date: 2021-05-05, Last modification date: 2024-03-06)

Primary citation

Beshore, D.C.,Adam, G.C.,Barnard, R.J.O.,Burlein, C.,Gallicchio, S.N.,Holloway, M.K.,Krosky, D.,Lemaire, W.,Myers, R.W.,Patel, S.,Plotkin, M.A.,Powell, D.A.,Rada, V.,Cox, C.D.,Coleman, P.J.,Klein, D.J.,Wolkenberg, S.E.
Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.
Acs Med.Chem.Lett., 12:540-547, 2021

PubMed Abstract: A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

PubMed: 33854701
DOI: 10.1021/acsmedchemlett.1c00074

Experimental method

X-RAY DIFFRACTION (1.8 Å)