Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need To Succeed
Open accessAbstract
Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis - SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution.
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Dose-limiting adverse effects such as cardiac toxicity associated with hERG K+ channel activation hinder progress of HDAC inhibitors in the clinic.
“Importantly, dose-limiting adverse effects such as cardiac toxicity associated with hERG K+ channel activation are hindering their progress in the clinic [133, 134].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [134]
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References 146 · Cited by 404
Research works printed but not linked: 1
- [119]Khan N Jeffers M Kumar S Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors Biochem J 409 2 581 589 2008 17868033
- Authors
- Gryder, B. E., Sodji, Q. H., & Oyelere, A. K.
- Affiliations
- Georgia Institute of Technology (US)
- Venue
- Future Medicinal Chemistry
- Publisher
- Informa UK Limited
- Published
- 2012-03
- Volume
- 4
- Issue
- 4
- Pages
- 505-524
- ISSN
- 1756-8919 (ISSN-L)
- 1756-8927
- PMC
- PMC3341130
- OpenAlex
- W2015645056
- Cited by
- 404
- References
- 146
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 22 · 2023: 22 · 2022: 24 · 2021: 26 · 2020: 45 · 2019: 30 · 2018: 23 · 2017: 39 · 2016: 34 · 2015: 32 · 2014: 26 · 2013: 32 · 2012: 9
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Future Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Georgia Institute of Technology (R01CA131217)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- histone deacetylase inhibitors, vorinostat, romidepsin, epigenetic modulation, histone acetylation, HDAC isoform selectivity, local drug delivery, cardiotoxicity, solid tumors, targeted cancer therapy
- MeSH terms
- Antineoplastic Agents, Chromatin, Clinical Trials as Topic, Histone Deacetylases, Humans, Neoplasms, Protein Isoforms, Histone Deacetylase Inhibitors
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