Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors

Smil, D.; Manku, Sukhdev; Chantigny, Yves; Leit, Silvana; Wahhab, Amal; Yan, Theresa P.; Fournel, Marielle; Maroun, Christiane R.; Li, Zuomei; Lemieux, Anne-Marie; Nicolescu, Alina; Rahil, Jubrail; Lefèbvre, Sylvain; Panetta, Anthony; Besterman, Jeffrey M.; Déziel, Robert

doi:10.1016/j.bmcl.2008.12.045

Cited by 80 publications

(42 citation statements)

References 22 publications

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“…Thus, HDAC6 has multiple biological functions through deacetylasedependent and -independent mechanisms modulating many cellular pathways relevant to normal and tumor cell growth, migration, and death. HDAC6 is an attractive target for potential cancer treatment.There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17).…”

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confidence: 99%

“…There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17).…”

mentioning

confidence: 99%

“…Tubacin has non-drug-like qualities, high lipophilicity, and difficult synthesis and has proved to be more useful as a research tool rather than as a potential drug (18). We and others (12)(13)(14)(15)19) have developed HDAC6-selective inhibitors whose pharmacokinetics, toxicity, and efficacy make them potentially more useful than tubacin as therapeutic agents. ACY-1215, 2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, a HDAC6-selective inhibitor, is currently being evaluated in clinical trials (http://clinicaltrials.gov).…”

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confidence: 99%

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Development of a histone deacetylase 6 inhibitor and its biological effects

Lee

Mahendran

Yao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

105

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Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.anticancer agents | epigenetics-based chemotherapy | drug discovery H istone deacetylase 6 (HDAC6) is unique among the eleven zinc-dependent HDACs in humans. HDAC6 is located in the cytoplasm, and it has two catalytic domains and an ubiquitinbinding domain at the C-terminal region (1-3). This study focused on the development of a HDAC6-selective inhibitor and its biological effects. The substrates of HDAC6 include nonhistone proteins such as α-tubulin, peroxiredoxin (PRX), cortactin, and heat shock protein 90 (Hsp90) but not histones (4-7). HDAC6 plays a key role in the regulation of microtubule dynamics including cell migration and cell-cell interactions. The reversible acetylation of Hsp90, a substrate of HDAC6, modulates its chaperone activity and, accordingly, the stability of survival and antiapoptotic factors, including epidermal growth factor receptor (EGFR), protein kinase AKT, proto-oncogene C-RAF, survivin, and other factors. HDAC6, through its ubiquitin-binding activity and interaction with other partner proteins, plays a role in the degradation of misfolded proteins by binding polyubiquitinated proteins and delivering them to the dynein and motor proteins for transport into aggresomes which are degraded by lysosomes (8-10). Thus, HDAC6 has multiple biological functions through deacetylasedependent and -independent mechanisms modulating many cellular pathways relevant to normal and tumor cell growth, migration, and death. HDAC6 is an attractive target for potential cancer treatment.There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17). Tubacin has non-drug-like qualities, high lipophilicity, and difficult synthesis and has proved to be more useful as a research tool rather than as a potential drug (18). We and others (12)(13)(14)(15)19) have developed HDAC6-selective inhibitors whose pharmacokinetics, toxicity, and efficacy make them potentially more useful than tubacin as therapeutic agents. ACY-1215, 2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, a HDAC6-selective inhibitor, is currently being evaluated in clinical trial...

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mentioning

confidence: 99%

“…There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Development of a histone deacetylase 6 inhibitor and its biological effects

Lee

Mahendran

Yao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

105

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“…Achiral compound 7a displayed no preferential a-tubulin acetylation over H3 acetylation than other chiral compounds (45), consequently the chiral center of such compounds is of great importance in selectivity and potency. By comparison with compounds 7b, 7c, 7d, 7e, 7i, 7j and 12a, 12b, 12c (Figure 7), the conclusion is that the most selective and potent compounds with such structural elements are characterized by the confi guration of the chiral centre rather than substituent 'R'.…”

Section: Chiral 34-dihydroquinoxalin-2(1h)-one and Piperazine-25-dimentioning

confidence: 97%

“…Novel 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates displaying selectivity and potency for HDAC6 have been designed and synthesized, they are evaluated to have about a 40-fold selectivity for HDAC6 over HDAC1 (45). In vitro enzyme assays with compounds of the 7 series with dihydroquinoxalin displayed higher potency than the 12 series with piperazine (45), the result showed that cap dihydroquinoxalin had a performance increase for greater selectivity than that of series 12.…”

Section: Chiral 34-dihydroquinoxalin-2(1h)-one and Piperazine-25-dimentioning

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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Privileged Structures in Drug Discovery

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Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors

Cited by 80 publications

References 22 publications

Development of a histone deacetylase 6 inhibitor and its biological effects

Development of a histone deacetylase 6 inhibitor and its biological effects

HDAC6: Physiological function and its selective inhibitors for cancer treatment

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