Rational Design of Non-Hydroxamate Histone Deacetylase Inhibitors

Suzuki, Takayoshi; Miyata, Naoki

doi:10.2174/138955706776876186

Cited by 29 publications

(32 citation statements)

References 47 publications

(105 reference statements)

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“…Structural characteristics of Potent HDAC inhibitor SAHA. [3,4] pounds were clustered into 8423 compound families of similar molecular descriptors, which are consistent with the reported 12 800 compound-occupying neurons (regions of topologically close structures) for 26.4 million compounds of up to 11 atoms, [47] and 2851 clusters for 171 045 natural products. [48] A total of 62 198 compounds extracted from the 7853 families that contain no known HDACi were used as the putative non-HDACi.…”

Section: Compound Collection and Dataset Constructionsupporting

confidence: 86%

“…small fatty acids, o-aminoanilides, electrophilic ketones, N-formyl hydroxylamines, thiols and mercaptoamides). [3] Table 1 shows examples of HDACi and their ZBGs together with reported potency ranges and problems. Some hydroxamate HDACi tend to show poor pharmacokinetics, [6] severe toxicity, [7] and low specificity towards HDAC isozymes.…”

Section: Introductionmentioning

confidence: 99%

“…thiol). [3] Hence, there is a strong need for searching new HDACi free of these problems from more diverse chemical libraries. [1,2] Efforts have been directed at expanded search of the chemical space, rational modification of linker and cap groups, and the introduction of pro-drugs.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Compound Collection and Dataset Constructionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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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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“…In fact, compound 144 with ω-(R) chirality was practically inactive on all HDAC isoforms, while its enantiomer 126 and the diastereoisomer 127, having both S configuration in the ω position, had comparable and good inhibitory potencies. With the lactam carboxamide in the ω position having the most favorable S configuration, the substituent improved inhibitory potency on all isoforms compared to the unsubstituted 15. This effect reflects the 26 On the other hand, the increase of inhibitory potency given by the lactam carboxamide substituent was greater for these thiol derivatives than for hydroxamic acid counterparts.…”

Section: ■ Results and Discussionmentioning

confidence: 92%

ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

et al. 2014

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A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ω-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.

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“…68,108,109) These selective inhibitors are intriguing both chemically and biologically, and are of interest as candidate therapeutic agents having few side effects. To date, X-ray crystal structures of human HDAC4, 110) HDAC7, 111) HDAC8, [73][74][75] SIRT2 112) and SIRT5 113) have been published.…”

Section: Resultsmentioning

confidence: 99%

Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

Suzuki

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members (HDAC1-11 and SIRT1-7) have been identified, but the functions of the HDAC isoforms are not yet fully understood. In addition, some of the HDAC isoforms have been suggested to be associated with various disease states, including cancer and neurodegenerative disorders. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. It was against this background that we initiated research programs to identify isoform-selective HDAC inhibitors. We designed HDAC inhibitors based on the three-dimensional structure of the enzyme and on the proposed catalytic mechanism of HDACs, and found several isoform-selective HDAC inhibitors. Furthermore, we elucidated the functions of HDAC6 by chemical genetic approaches using these inhibitors. The results of this research also suggested the feasibility of using isoform-selective HDAC inhibitors as therapeutic agents.

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Rational Design of Non-Hydroxamate Histone Deacetylase Inhibitors

Cited by 29 publications

References 47 publications

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

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

ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

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