Toward Isozyme-Selective Inhibitors of Histone Deacetylase As Therapeutic Agents for the Treatment of Cancer

Ononye, Sophia N.; Heyst, Michael van; Falcone, Eric M; Anderson, Amy C.; Wright, Dennis L.

doi:10.4155/ppa.12.21

Cited by 24 publications

(20 citation statements)

References 50 publications

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“…Although yet to be proven, it is generally thought that HDACi with increased isoform-selectivity and potency would be safer agents with reduced side effects and could lead to superior clinical outcomes, because such selective compounds would only target HDAC activities that are dysregulated in a particular type of cancer without causing unnecessary toxicity stemming from inhibiting other HDAC isoforms. Thus, there have been significant efforts in drug development to identify HDACi with greater isozyme-specificity (Ononye, et al, 2012). The aminobenzamide class of HDACi is selective to class I HDACs (HDACs 1–3) and displays unique slow-on/slow-off HDAC-binding kinetics (Beconi, et al, 2012; Chou, et al, 2008; Lauffer, et al, 2013; Newbold, et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

Wang

Stowe

Pinello

et al. 2015

Chemistry & Biology

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SUMMARY Inhibitors of histone deacetylases (HDACi) hold a considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications.

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Section: Introductionmentioning

confidence: 99%

Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

Wang

Stowe

Pinello

et al. 2015

Chemistry & Biology

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“…13 HDACs exist in several classes and with many isozymes, with current research focused on the discovery and development of isozyme selective epigenetic modulators to avoid the side effects inherent in non-selective inhibitors. 14–16 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Gromek

deMayo

Maxwell

et al. 2016

Bioorganic & Medicinal Chemistry

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Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure-activity relationships will be of interest for future studies on cell proliferation and immune modulation.

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“…19 HDAC-selective inhibitors are being developed in the hope of mediating potent antitumor responses and reducing toxicities. 20 However, whether more selective HDACis will deliver on this premise remains to be determined. Transient depletion of individual HDACs in human tumor cells using small interfering RNA has not conclusively demonstrated whether antitumor actions of broadacting HDACis can be phenocopied by loss of individual or multiple HDACs.…”

Section: Introductionmentioning

confidence: 99%

Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies

Matthews

Mehdipour

Cluse

et al. 2015

Blood

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Key Points• Genetic studies suggest HDAC3-selective suppression may prove useful for treatment of hematological tumors but will not induce apoptosis.• Genetic and pharmacological cosuppression of HDAC1 with HDAC2 induces a potent proapoptotic response of tumor cells.Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;Nras G12D; PML-RARa acute promyelocytic leukemia [APL] cells) and Em-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, caspase inhibition, or knockout of Cdkn1a in Em-Myc lymphoma, and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Em-Myc lymphoma and induced differentiation in APL. Genetic codepletion of Hdac1 with Hdac2 was pro-apoptotic in Em-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells, suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that codepletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies. (Blood. 2015;126(21):2392-2403

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Toward Isozyme-Selective Inhibitors of Histone Deacetylase As Therapeutic Agents for the Treatment of Cancer

Cited by 24 publications

References 50 publications

Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies

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