A series of novel, potent, and selective histone deacetylase inhibitors

Jones, Philip; Altamura, Sergio; Chakravarty, Prasun K.; Cecchetti, Ottavia; Francesco, Raffaele De; Gallinari, Paola; Ingenito, Raffaele; Meinke, Peter T.; Petrocchi, Alessia; Rowley, Michael; Serafini, Sergio; Steinkühler, Christian

doi:10.1016/j.bmcl.2006.09.002

Cited by 70 publications

(51 citation statements)

References 18 publications

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“…We have used apicidin as a starting point for a drug discovery program and were to evolve a series of potent, low molecular weight, non-hydroxamic acid HDACi's, exemplified by 4 (Figure 4), which is selective for HDACs 1, 2, 3 and 6, and displays only weak or no activity on HDACs 4, 5, 7 and 8 [164]. Furthermore, 4 showed submicromolar activity against several human tumor cell lines.…”

Section: Classes Of Hdaci's and Their Anticancer Propertiesmentioning

confidence: 99%

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

et al. 2007

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Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.

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Section: Classes Of Hdaci's and Their Anticancer Propertiesmentioning

confidence: 99%

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

et al. 2007

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“…As to acyclic caps, derivatives containing the key LAoda aliphatic side chain in apicidin have been proved as good cap groups for design of none tetra-peptide HDACi. [89] Similar structures like CID:10073606, CID:10476346, CID: 11567826, CID:11569749, CID:11582665 in Figure 5 were found from the SVM virtual hits which may serve as possible good caps alternative to LAoda. To further evaluate whether SVM identify HDACi rather than membership of certain compound families, Compound family distribution of the identified HDACi were analyzed.…”

Section: Evaluation Of the Predicted Tetra-peptide Cap Of Svm Virtualmentioning

confidence: 99%

Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach

Liu

Song

Zhang

et al. 2010

Molecular Informatics

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Histone deacetylase inhibitors (HDACi) have been successfully used for the treatment of cancers and other diseases. Search for novel type ZBGs and development of non-hydroxamate HDACi has become a focus in current research. To complement this, it is desirable to explore a virtual screening (VS) tool capable of identifying different types of potential inhibitors from large compound libraries with high yields and low false-hit rates similar to HTS. This work explored the use of support vector machines (SVM) combined with our newly developed putative non-inhibitor generation method as such a tool. SVM trained by 702 pre-2008 hydroxamate HDACi and 64334 putative non-HDACi showed good yields and low false-hit rates in cross-validation test and independent test using 220 diverse types of HDACi reported since 2008. The SVM hit rates in scanning 13.56 M PubChem and 168K MDDR compounds are comparable to HTS rates. Further structural analysis of SVM virtual hits suggests its potential for identification of non-hydroxamate HDACi. From this analysis, a series of novel ZBG and cap groups were proposed for HDACi design.

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“…From the study of Jones et al (52,53), we found a potent HDAC inhibitor with a methylketone ZBG. Based on their study, researchers tried to find if compounds with the sulfamide at the e-nitrogen are potent and selective for HDAC6 inhibition.…”

Section: Sulfamidesmentioning

confidence: 99%

HDAC6: Physiological function and its selective inhibitors for cancer treatment

Yang

Zhang

et al. 2013

Drug Discov Ther

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Acetylation and deacetylation of histones are important in regulating gene expression and play a key role in modification of gene transcription. Specific HDACs isoforms can be regarded as a target for cancer therapy avoiding side-effects, HDAC6 with a unique physiological function and structure has become a hot issue recently. The unique isoform HDAC6 is involved in tumorigenesis, development and metastasis through tubulin, HSP90, invasin and ubiquitin-protein.Here we review the structure elements, biological function, and recent selective inhibitors of HDAC6, and study the structure-activity and structureselectivity relationship.

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A series of novel, potent, and selective histone deacetylase inhibitors

Cited by 70 publications

References 18 publications

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach

HDAC6: Physiological function and its selective inhibitors for cancer treatment

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