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Structural Requirements of Histone Deacetylase Inhibitors: SAHA Analogs Modified on the Hydroxamic Acid
Author(s) -
Bieliauskas Anton V.,
Weerasinghe Sujith V. W.,
Negmeldin Ahmed T.,
Pflum Mary Kay H.
Publication year - 2016
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500472
Subject(s) - hydroxamic acid , chemistry , vorinostat , moiety , hdac1 , histone deacetylase , stereochemistry , histone deacetylase inhibitor , docking (animal) , enzyme , selectivity , combinatorial chemistry , biochemistry , histone , catalysis , medicine , nursing , gene
Histone deacetylase (HDAC) proteins have emerged as targets for anti‐cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most of the 11 human HDAC proteins, the creation of selective inhibitors has been studied intensely. Recently, inhibitors selective for HDAC1 and HDAC2 were reported where selectivity was attributed to interactions between substituents on the metal binding moiety of the inhibitor and residues in the 14‐Å internal cavity of the HDAC enzyme structure. Based on this earlier work, we synthesized and tested SAHA analogs with substituents on the hydroxamic acid metal binding moiety. The N ‐substituted SAHA analogs displayed reduced potency and solubility, but greater selectivity, compared to SAHA. Docking studies suggested that the N ‐substituent accesses the 14‐Å internal cavity to impart preferential inhibition of HDAC1. These studies with N ‐substituted SAHA analogs are consistent with the strategy exploiting the 14‐Å internal cavity of HDAC proteins to create HDAC1/2 selective inhibitors.