|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
17
|
|
pubmed:dateCreated |
2005-8-18
|
|
pubmed:abstractText |
Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn(2+)-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC(50) in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 microM was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.
|
|
pubmed:grant |
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylases,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxamic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/N-hydroxy-4-(4-phenylbutyrylamino)be...,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylbutyrates,
http://linkedlifedata.com/resource/pubmed/chemical/trichostatin A
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Aug
|
|
pubmed:issn |
0022-2623
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
25
|
|
pubmed:volume |
48
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
5530-5
|
|
pubmed:dateRevised |
2009-11-19
|
|
pubmed:meshHeading |
pubmed-meshheading:16107152-Acetylation,
pubmed-meshheading:16107152-Benzamides,
pubmed-meshheading:16107152-Cell Cycle Proteins,
pubmed-meshheading:16107152-Cell Line, Tumor,
pubmed-meshheading:16107152-Cell Survival,
pubmed-meshheading:16107152-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:16107152-Histone Deacetylase Inhibitors,
pubmed-meshheading:16107152-Histone Deacetylases,
pubmed-meshheading:16107152-Histones,
pubmed-meshheading:16107152-Humans,
pubmed-meshheading:16107152-Hydroxamic Acids,
pubmed-meshheading:16107152-Models, Molecular,
pubmed-meshheading:16107152-Molecular Structure,
pubmed-meshheading:16107152-Phenylbutyrates,
pubmed-meshheading:16107152-Quantitative Structure-Activity Relationship,
pubmed-meshheading:16107152-Stereoisomerism
|
|
pubmed:year |
2005
|
|
pubmed:articleTitle |
Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.
|
|
pubmed:affiliation |
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, N.I.H., Extramural
|
