Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

Ho, Terence C. S.; Chan, Alex H. Y.; Ganesan, A.

doi:10.1021/acs.jmedchem.0c00830

Cited by 525 publications

(491 citation statements)

References 176 publications

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“…The four class I HDACs were reported to act on histones where the vast majority of cellular lysine acetylation takes place [ 28 ]. Moreover, even though class IIa HDACs might still play a part in the histone deacetylation process through complex formation with HDAC3, it is now questionable whether they exert any independent deacetylase activity [ 29 ]. The class IIb isoform HDAC6 regulates Hsp90, tau and the cytoskeleton through its interactions with tubulin and cortactin, and recognizes ubiquitinated proteins to induce aggresome formation [ 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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Section: Introductionmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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“…One such enzyme is the histone deacetylase, HDAC3, which was recently demonstrated to directly deacetylate MutSβ and stimulate expansions [118]. Potent inhibitors already exist that selectively block HDAC3 activity [119][120][121][122][123]. Several of these HDAC3 inhibitors have been shown in mouse studies to alleviate motor and cognitive symptoms of HD, and also to inhibit striatal Htt expansions [120,124,125].…”

Section: Connections To Therapymentioning

confidence: 99%

New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

Lahue

2020

Neuronal Signaling

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Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome wide association studies have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augments the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

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“…The crystal structures of HDACs and PI3Ks are available in the Protein Data Bank (PDB). Several works describe the structural aspects for the HDAC [18,19,86–88] and PI3K [35,89,90] selective inhibition.…”

Section: Exploring Selectivity In Multitarget Hdac and Pi3k Inhibitorsmentioning

confidence: 99%

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

2020

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The discovery of histone deacetylase (HDAC) inhibitors is a hot topic in the medicinal chemistry community regarding cancer research. This is related primarily to two factors: success in the clinic, e. g., the four FDA‐approved HDAC inhibitors, and strong versatility to combine their pharmacophoric features to design new hybrid compounds with multitarget profiles. Thus, the selection of adequate pharmacophores to combine, i. e., combining targets that can result in a synergistic effect, is desirable, as it increases the probability of discovering a new useful therapeutic strategy. In this work, we highlight the design of multitarget HDAC/PI3K inhibitors. Although this approach is still in its early stages, many significant works have described the design and pharmacological evaluation of this new promising class of multitarget inhibitors, where compound CUDC‐907, which is already in clinical trials, stands out. Therefore, the question emerges of whether there still space for the design and evaluation of new multitarget HDAC/PI3K inhibitors. When considering the selectivity profile of the described multitarget compounds, the answer appears to be in the affirmative, especially since the first examples of compounds with a certain selectivity profile only recently appeared in 2020.

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Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

Cited by 525 publications

References 176 publications

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

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