Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6

ACS Omega
Mohamed D M TraoréYung-Sing Wong

Abstract

Little is known about the biological and structural features that govern the isoform selectivity for class I histone deacetylases (HDACs) over HDAC6. In addition to that for known inhibitors, like benzamides, psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was also observed for naturally occurring cyclopeptide HDAC inhibitors with an aliphatic flexible linker and ketonelike zinc-binding group (ZBG). The present study reports that this isoform selectivity is mainly due to the linker and ZBG, as replacement of the cyclopeptide cap region by a simple aniline retained class I HDAC isoform selectivity toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to explain this selectivity and suggests different behaviors of the flexible linker on HDAC1 and HDAC6 pockets, which may influence, on the basis of the strength of the ZBG, its coordination with the zinc ion.

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Citations

Jun 2, 2018·Current Medicinal Chemistry·Faria SultanaAhmed Kamal
Nov 25, 2020·Bioorganic & Medicinal Chemistry Letters·Qinghua Ren, Wenqian Gao
Mar 10, 2021·Bioorganic & Medicinal Chemistry Letters·Qinghua Ren, Wenqian Gao
Sep 8, 2021·ACS Infectious Diseases·Jennifer E CollinsDebopam Chakrabarti

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Methods Mentioned

BETA
acetylation
ubiquitination
histone acetylation
X-ray
NMR
column chromatography
FCS

Software Mentioned

GOLD
MOE
GraphPad Prism
Gaussian09
MOE Align
Antechamber of Amber
Sybyl X
xleap
AMBER12
SAHA

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