Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Varghese, Sheeba; Senanayake, Thulani; Murray-Stewart, Tracy; Doering, Kim; Fraser, Alison V.; Casero, Robert A.; Woster, Patrick M.

doi:10.1021/jm701384x

Cited by 32 publications

(48 citation statements)

References 31 publications

(113 reference statements)

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“…Taken together, these data strongly suggest that 10 causes significant up regulation of the expression of aberrantly silenced genes in leukemia cells in vitro, which in turn leads to a cytotoxic response. These observations are consistent with data previously published by us 13, 14 and by other research groups. 2, 17 We are currently assessing the antitumor effects of 10 in MV-4-11 leukemia cells in combination with standard antitumor agents such as the deoxynucleotide methyltransferase inhibitor 5-azacytidine.…”

Section: Introductionsupporting

confidence: 94%

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Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group

Woster

2015

Med. Chem. Commun.

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Small molecules featuring a hydroxamic acid or a benzamide zinc binding group (ZBG) are the most thoroughly studied histone deacetylase (HDAC) inhibitors. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety and potential metabolic toxicity of the aniline portion of benzamide HDAC inhibitors have stimulated research efforts aimed at discovering alternative ZBGs. Here we report the 2-(oxazol-2-yl)phenol moiety as a novel ZBG that can be used to produce compounds that are potent HDAC inhibitors. A series of analogues with this novel ZBG have been synthesized, and these analogues exhibit selective inhibition against HDAC1 as well as the class IIb HDACs (HDAC6 and HDAC10). Compound 10 possesses an IC50 value of 7.5 μM in the MV-4-11 leukemia cell line, and induces a comparable amount of acetylated histone 3 lysine 9 (H3K9) and p21Waf1/CIP1 as 0.5 μM of SAHA. Modeling of compound 10 in the active site of HDAC2 demonstrates that the 2-(oxazol-2-yl)phenol moiety has a zinc-binding pattern similar to benzamide HDAC inhibitors.

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Section: Introductionsupporting

confidence: 94%

“…These results are consistent with our earlier observations for differences in potency between hydroxamic acid- and benzamide-based histone deacetylase inhibitors. 13, 14 …”

Section: Introductionmentioning

confidence: 99%

Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group

Woster

2015

Med. Chem. Commun.

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“…The data from studies with these compounds demonstrate that minor structural modifications can result in significantly altered biological responses to the individual polyamine analogues. Additionally, these studies have validated the strategy that reactive functional groups can be added to the polyamine backbone to facilitate the entry of such conjugates into the cell through the polyamine transport system, leading to the synthesis of multiple compounds exploiting this strategy (Refs 121, 122, 123, 124). …”

Section: Clinical Implications and Applicationsmentioning

confidence: 90%

Polyamines and cancer: implications for chemotherapy and chemoprevention

Nowotarski

Woster

Casero

2013

Expert Rev. Mol. Med.

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263

222

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Polyamines are small organic cations that are essential for normal cell growth and development in eukaryotes. Under normal physiological conditions, intracellular polyamine concentrations are tightly regulated through a dynamic network of biosynthetic and catabolic enzymes and a poorly characterized transport system. This precise regulation ensures that the intracellular concentration of polyamines is maintained within strictly controlled limits. It has frequently been observed that the metabolism of, and the requirement for, polyamines in tumours is frequently dysregulated. Elevated levels of polyamines have been associated with breast, colon, lung, prostate, and skin cancers, and altered levels of the rate limiting enzymes in both biosynthesis and catabolism have been observed. Based on these observations and the absolute requirement for polyamines in tumour growth, the polyamine pathway is a rational target for chemoprevention and chemotherapeutics. Here we describe the recent advances made in the polyamine field and focus on the roles of polyamines and polyamine metabolism in neoplasia through a discussion of the current animal models for the polyamine pathway, chemotherapeutic strategies that target the polyamine pathway, chemotherapeutic clinical trials for polyamine pathway specific drugs, and ongoing clinical trials targeting polyamine biosynthesis.

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“…Various chemical modifications have incorporated solubilizing functional groups, which may improve pharmacokinetic properties. Considerable efforts are being made to develop isoform-selective deacetylase inhibitors such as tubacin, which selectively inhibits HDAC6, and PC-34051, a selective HDAC8 inhibitor [18,50,53]. …”

Section: Histone Deacetylase Inhibitors (Hdaci)mentioning

confidence: 99%

“…Indeed, there is an ongoing substantial effort to develop HDAC6 isoform selective inhibitors that may be clinically useful in treating cancers and possibly other diseases [50]. …”

Section: Mechanism Of Action Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs

Marks

2010

Expert Opinion on Investigational Drugs

254

241

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Importance of the field Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs. Area covered in this review This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death. What the reader will gain There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs. Take home message There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents.

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Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Cited by 32 publications

References 31 publications

Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group

Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group

Polyamines and cancer: implications for chemotherapy and chemoprevention

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs

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