Peptide Based Macrocycles: Selective Histone Deacetylase Inhibitors with Antiproliferative Activity

Rajak, Harish; Singh, A. Jonathan; Dewangan, P.K.; Patel, Vijay K.; Jain, Deepak Kumar; Tiwari, Sarika; Veerasamy, Ravichandran; Sharma, Prabodh Chander

doi:10.2174/0929867311320140006

Cited by 27 publications

(13 citation statements)

References 126 publications

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“…Comprehensive reviews on the design and discovery of selective HDAC inhibitors have been covered elsewhere [80,81,82,83,84], hence, will only be mentioned briefly, herein.…”

Section: Selective Hdac Inhibitorsmentioning

confidence: 99%

Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors

Thomas

2014

Pharmaceuticals

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Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various experimental models of neurological disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biological roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington’s disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclinical efficacy of these compounds remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.

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“…Comprehensive reviews on the design and discovery of selective HDAC inhibitors have been covered elsewhere [80,81,82,83,84], hence, will only be mentioned briefly, herein.…”

Section: Selective Hdac Inhibitorsmentioning

confidence: 99%

Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors

Thomas

2014

Pharmaceuticals

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“…Cyclic peptide‐based HDACIs are among the most structurally complex and the most potent class of HDACIs. Modification of the cap group moiety of these HDACIs outcomes in modulation of biological activity with increased isoform selectivity between different HDAC isoforms . Based on their macrocyclic moieties, these HDACIs can be subdivided into two families: cyclic tetrapeptides and bicyclic depsipeptides.…”

Section: Chemical Classes Of Histone Deacetylases Inhibitorsmentioning

confidence: 99%

“…Modification of the cap group moiety of these HDACIs outcomes in modulation of biological activity with increased isoform selectivity between different HDAC isoforms. [104][105][106] Based on their macrocyclic moieties, these HDACIs can be subdivided into two families: cyclic tetrapeptides and bicyclic depsipeptides. The first class is formed by a cyclic scaffold of D-and L-amino acids and includes trapoxin, 107 apicidin, 108 azumamide, 109 and HC-toxin.…”

Section: Macrocyclesmentioning

confidence: 99%

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Zagni

Floresta

Monciino

et al. 2017

Medicinal Research Reviews

110

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Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T-cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.

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“…Interestingly, the skeletons with macrocyclic Cap have better inhibitory activities against HDAC Class I than Class II, among which the macrocyclic peptide inhibitors account for a large proportion (Mwakwari et al, 2010;Rajak et al, 2013;Tapadar et al, 2015). As inhibiting class II HDACs (represented by HDAC6) can lead to unwanted toxic and side effects (especially serious cardiac toxicity) (Roche and Bertrand, 2016), targeting specific HDAC subtypes has shown great therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics

Wang

Ren

et al. 2020

Front. Mol. Biosci.

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Glioblastoma (GBM) is the most common and aggressive intracranial malignant brain tumor, and the abnormal expression of HDAC1 is closely correlated to the progression, recurrence and metastasis of GBM cells, making selective inhibition of HDAC1 a promising strategy for GBM treatments. Among all available selective HDAC1 inhibitors, the macrocyclic peptides have gained great attention due to their remarkable inhibitory selectivity on HDAC1. However, the binding mechanism underlying this selectivity is still elusive, which increases the difficulty of designing and synthesizing the macrocyclic peptide-based anti-GBM drug. Herein, multiple computational approaches were employed to explore the binding behaviors of a typical macrocyclic peptide FK228 in both HDAC1 and HDAC6. Starting from the docking conformations of FK228 in the binding pockets of HDAC1&6, relatively long MD simulation (500 ns) shown that the hydrophobic interaction and hydrogen bonding of E91 and D92 in the Loop2 of HDAC1 with the Cap had a certain traction effect on FK228, and the sub-pocket formed by Loop1 and Loop2 in HDAC1 could better accommodate the Cap group, which had a positive effect on maintaining the active conformation of FK228. While the weakening of the interactions between FK228 and the residues in the Loop2 of HDAC6 during the MD simulation led to the large deflection of FK228 in the binding site, which also resulted in the decrease in the interactions between the Linker region of FK228 and the previously identified key amino acids (H134, F143, H174, and F203). Therefore, the residues located in Loop1 and Loop2 contributed in maintaining the active conformation of FK228, which would provide valuable hints for the discovery and design of novel macrocyclic polypeptide HDAC inhibitors.

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Peptide Based Macrocycles: Selective Histone Deacetylase Inhibitors with Antiproliferative Activity

Cited by 27 publications

References 126 publications

Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors

Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics

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