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Title

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

Authors
Traoré, Mohamed D M
Maynadier, Marjorie
Wein, Sharon
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Published in ACS Omega. 2017, vol. 2, no. 4, p. 1550-1562
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.
Identifiers
PMID: 30023639
Full text
Article (Published version) (2.5 MB) - public document Free access
Structures
Research group Pharmacognosie
Projects ARCANE project No. ANR-11-LABX-003
FNS: P300P3 158507
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(ISO format)
TRAORÉ, Mohamed D M et al. Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6. In: ACS Omega, 2017, vol. 2, n° 4, p. 1550-1562. https://archive-ouverte.unige.ch/unige:120580

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Deposited on : 2019-07-10

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