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Structural Requirements Of Histone Deacetylase Inhibitors: SAHA Analogs Modified On The Hydroxamic Acid

Anton V. Bieliauskas, Sujith V. W. Weerasinghe, Ahmed T Negmeldin, M. K. Pflum
Published 2016 · Chemistry, Medicine

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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.
This paper references
10.1016/S0040-4039(01)80314-2
Alkylation of n-benzyloxyureas and carbamates
R. Sulsky (1989)
Python: a programming language for software integration and development.
M. Sanner (1999)
10.1038/43710
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
M. S. Finnin (1999)
10.1016/S0968-0004(00)01718-7
25 years after the nucleosome model: chromatin modifications.
J. Wu (2000)
10.1080/00304940109356608
A NEW FACILE AND EXPEDITIOUS SYNTHESIS OF N-HYDROXY-N′-PHENYLOCTANEDIAMJDE, A POTENT INDUCER OF TERMINAL CYTODIFFERECNTIATION
A. Mai (2001)
10.1073/PNAS.0404603101
Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.
Alessandro Vannini (2004)
10.1016/J.STR.2004.04.012
Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases.
J. R. Somoza (2004)
10.1021/JM0498497
On the function of the 14 A long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors.
D. Wang (2004)
10.1016/J.JMB.2004.02.006
Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis.
Ivan V. Gregoretti (2004)
10.1021/JA0400382
o-Iodoxybenzoic acid (IBX) as a viable reagent in the manipulation of nitrogen- and sulfur-containing substrates: scope, generality, and mechanism of IBX-mediated amine oxidations and dithiane deprotections.
K. Nicolaou (2004)
10.1002/MED.20024
Histone deacetylation in epigenetics: An attractive target for anticancer therapy
A. Mai (2005)
10.1021/JM0505011
Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases.
D. Wang (2005)
10.1038/nrc1779
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
S. Minucci (2006)
10.1038/nbt0107-17
HDAC inhibitors overcome first hurdle
K. Garber (2007)
10.1016/J.BMCL.2007.01.117
Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid.
Anton V. Bieliauskas (2007)
10.1021/JM701079H
Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
O. Moradei (2007)
10.1038/sj.leu.2404464
Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?
T. Karagiannis (2007)
10.1039/b703830p
Isoform-selective histone deacetylase inhibitors.
Anton V. Bieliauskas (2008)
10.1074/jbc.M707362200
Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity*
A. Schuetz (2008)
10.1042/BJ20070779
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.
Nagma Khan (2008)
10.1016/J.BMCL.2007.11.047
Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2).
David J Witter (2008)
10.1074/jbc.M803514200
Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain*
M. Bottomley (2008)
10.1021/jm7015254
Structural origin of selectivity in class II-selective histone deacetylase inhibitors.
Guillermina L Estiú (2008)
10.1016/j.bmcl.2007.12.031
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
Joey L Methot (2008)
10.1016/j.bmcl.2009.03.101
Exploring bis-(indolyl)methane moiety as an alternative and innovative CAP group in the design of histone deacetylase (HDAC) inhibitors.
G. Giannini (2009)
10.1002/jcc.21256
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
G. Morris (2009)
10.1016/j.canlet.2009.02.013
Isoform-specific histone deacetylase inhibitors: the next step?
S. Balasubramanian (2009)
10.1016/j.bmcl.2010.03.091
Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides.
J. C. Bressi (2010)
10.1016/j.bmc.2010.03.078
Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids.
Marc Lamblin (2010)
10.1016/j.bmcl.2011.01.128
On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis.
S. Haider (2011)
10.1016/j.bmcl.2011.08.027
The structural requirements of histone deacetylase inhibitors: Suberoylanilide hydroxamic acid analogs modified at the C3 position display isoform selectivity.
S. E. Choi (2011)
10.1038/nature10728
Structure of HDAC3 bound to corepressor and inositol tetraphosphate
P. Watson (2012)
10.1016/j.bmcl.2012.09.093
The structural requirements of histone deacetylase inhibitors: suberoylanilide hydroxamic acid analogs modified at the C6 position.
S. E. Choi (2012)
10.1016/j.bmc.2013.04.036
Structural basis for the design and synthesis of selective HDAC inhibitors.
Simone Di Micco (2013)
10.1016/j.molcel.2013.05.020
Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates
C. Millard (2013)
10.1021/jm401837e
Mutagenesis Studies of the 14 Å Internal Cavity of Histone Deacetylase 1: Insights toward the Acetate-Escape Hypothesis and Selective Inhibitor Design
M. Wambua (2014)



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