Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors

Shultz, Michael D.; Cao, Xueying; Chen, Christine; Cho, Young Shin; Davis, Nicole R.; Eckman, J.; Fan, Jianmei; Fekete, Alex; Firestone, Brant; Flynn, Julie; Green, Jack; Growney, Joseph D.; Holmqvist, Mats; Hsu, Meier; Jansson, Daniel; Jiang, Lei; Kwon, Paul; Liu, Gang; Lombardo, Franco; Lü, Qiang; Majumdar, Dyuti; Meta, Christopher; Perez, Lawrence; Pu, Minying; Ramsey, Tim; Remiszewski, Stacy; Skolnik, Suzanne; Traebert, Martin; Urbán, László; Uttamsingh, Vinita; Wang, Ping; Whitebread, Steven; Whitehead, Lewis; Yan‐Neale, Yan; Yao, Yung-Mae; Zhou, Liping; Atadja, Peter

doi:10.1021/jm200388e

Cited by 56 publications

(39 citation statements)

References 72 publications

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“…Outside of the ability of HDAC3 to regulate genomic stability (7), mouse knockout studies have also shown that HDAC3 is necessary for maintenance of several metabolic functions in both cardiac and hepatic tissues (38, 39). One particular problem with current clinically available HDAC inhibitors is that they also bind and inhibit the hERG ion channel, which has been linked with QT prolongation (40). This off-target binding can lead to cardiac arrhythmia and is potentially fatal.…”

Section: Discussionmentioning

confidence: 99%

“…This off-target binding can lead to cardiac arrhythmia and is potentially fatal. Newer inhibitors are now being screened not only for their abilities to block HDAC function, but also for their abilities to block hERG activity as well (40, 41). An HDAC inhibitor that structurally cannot inhibit HDAC3 and cannot bind hERG, then, would be of considerable therapeutic interest.…”

Section: Discussionmentioning

confidence: 99%

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Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL

Stubbs

Kim

Bariteau

et al. 2015

Clinical Cancer Research

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Purpose Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small molecule inhibitors that target epigenetic mechanisms. Experimental Design A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B cell malignancy derived cell lines and a pediatric B-ALL were used to demonstrate pharmacological efficacy. Results Non-selective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform specific HDACi indicated that targeting HDAC1-3 with class I HDAC specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo while it was far less effective against other B-cell derived malignancies. Conclusions Here we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL

Stubbs

Kim

Bariteau

et al. 2015

Clinical Cancer Research

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“…These multiple pathways occurring alone and in multiple combinations lead to the observed complexity. Knowledge of the soft spot of metabolism contributed to the design of novel deacetylase inhibitors with improved metabolic properties and no doselimiting cardiac effects (Shultz et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Fredenhagen

Kittelmann²,

Oberer³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that is currently being evaluated in phase III clinical trials for treatment of Hodgkin's lymphoma and multiple myeloma. Under catalysis of recombinant human CYP3A4 and CYP2D6 coexpressed with human cytochrome P450 reductase in Escherichia coli JM109, five metabolites of panobinostat were produced via whole-cell biotransformation. The structures of the metabolites were elucidated with the spectroscopic methods mass spectrometry (MS) and NMR and revealed an oxidative cyclization of the ethyl-amino group to the methylindole moiety. The MS 2 spectrum of the cyclized metabolite showed a base peak, where the closed ring is reopened and that, taken as sole base for structure proposals, would have lead to wrong conclusions. The metabolites were substantially less potent deacetylase inhibitors than the parent compound.

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“…The greatest cardio-toxicity is, however, observed after treatment with hydroxamic-derivative HDACi. Again, it is unclear as to whether hydroxamic derivatives interact preferentially with (hERG)K + channels or whether their broad-spectrum activity against all HDACs could exacerbate cardiac side effects (195).…”

Section: Side Effects Of Hdacimentioning

confidence: 99%

Targeting Histone Deacetylases in Diseases: Where Are We?

Benedetti

Conte

Altucci

2015

Antioxidants & Redox Signaling

102

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Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoformdirected HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. Antioxid. Redox Signal. 23, 99-126.Shaping the Epigenome E pigenetic mechanism(s) allow genetically identical cells to adopt different phenotypes regulating transcriptional availability of the genome through differential chromatin marking and packaging (137), creating a network of mutually reinforcing or counteracting signals (192). A key aspect of epigenetics is that chromatin marks can be preserved and/or changed according to environmental, developmental, or pathological needs. These very complex and plastic steps are achieved via the activity of initiators (such as long noncoding RNA), writers (which establish the epigenetic mark, such as histone acetyltransferases), readers (which interpret the epi-mark), and erasers (which remove the epi-mark, such as histone deacetylases, or HDACs) (41, 232). In concert, remodelers (which reposition nucleosomes) and insulators (which build boundaries between epi-domains) create, maintain, and modulate the three-dimensional structure of networking within a cell (223). It is now clear that genetic and epigenetic mechanisms influence each other, cooperating to enable the acquisition of hallmarks of human cancer (89). The frequency of epi-target mutations seen in cancers underlines the relevance of mutations in epigenetic modifiers in cancer (213) and corroborates the concept that deregulation of epigenetic cont...

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Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors

Cited by 56 publications

References 72 publications

Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL

Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL

Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Targeting Histone Deacetylases in Diseases: Where Are We?

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