Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance

Ganai, Shabir Ahmad

doi:10.3109/13880209.2015.1135966

Cited by 18 publications

(5 citation statements)

References 62 publications

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“…While HATs favor the transcriptional activation via chromatin decondensation, HDACs promote chromatin condensation and subsequent gene silencing (Yang and Seto, 2007 ). The opposing activities of HATs and HDACs regulate acetylation homeostasis that plays a crucial role in governing various gene expression programs (Ropero and Esteller, 2007 ; Ganai, 2016a ). HDACs are conjugated enzymes modulating both histone and non-histone substrates and act as corepressors in transcriptional events (Yang and Seto, 2008 ; Mottamal et al, 2015 ; Ganai, 2016b ).…”

Section: Introductionmentioning

confidence: 99%

“…Romidepsin followed SAHA in gaining approval and is currently used against CTCL and peripheral T-cell lymphoma (PTCL) (Ververis et al, 2013 ). Belinostat, the third HDAC inhibitor has been approved for relapsed/refractory PTCL (Ververis et al, 2013 ; Ganai, 2016a ). The fourth approved inhibitor panobinostat is currently active against multiple myeloma (Ganai, 2016c ).…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

Ganai

Abdullah

Rashid

et al. 2017

Front. Mol. Neurosci.

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Histone deacetylases (HDACs) regulate epigenetic gene expression programs by modulating chromatin architecture and are required for neuronal development. Dysregulation of HDACs and aberrant chromatin acetylation homeostasis have been implicated in various diseases ranging from cancer to neurodegenerative disorders. Histone deacetylase inhibitors (HDACi), the small molecules interfering HDACs have shown enhanced acetylation of the genome and are gaining great attention as potent drugs for treating cancer and neurodegeneration. HDAC2 overexpression has implications in decreasing dendrite spine density, synaptic plasticity and in triggering neurodegenerative signaling. Pharmacological intervention against HDAC2 though promising also targets neuroprotective HDAC1 due to high sequence identity (94%) with former in catalytic domain, culminating in debilitating off-target effects and creating hindrance in the defined intervention. This emphasizes the need of designing HDAC2-selective inhibitors to overcome these vicious effects and for escalating the therapeutic efficacy. Here we report a top-down combinatorial in silico approach for identifying the structural variants that are substantial for interactions against HDAC1 and HDAC2 enzymes. We used extra-precision (XP)-molecular docking, Molecular Mechanics Generalized Born Surface Area (MMGBSA) for predicting affinity of inhibitors against the HDAC1 and HDAC2 enzymes. Importantly, we employed a novel in silico strategy of coupling the state-of-the-art molecular dynamics simulation (MDS) to energetically-optimized structure based pharmacophores (e-Pharmacophores) method via MDS trajectory clustering for hypothesizing the e-Pharmacophore models. Further, we performed e-Pharmacophores based virtual screening against phase database containing millions of compounds. We validated the data by performing the molecular docking and MM-GBSA studies for the selected hits among the retrieved ones. Our studies attributed inhibitor potency to the ability of forming multiple interactions and infirm potency to least interactions. Moreover, our studies delineated that a single HDAC inhibitor portrays differential features against HDAC1 and HDAC2 enzymes. The high affinity and selective HDAC2 inhibitors retrieved through e-Pharmacophores based virtual screening will play a critical role in ameliorating neurodegenerative signaling without hampering the neuroprotective isoform (HDAC1).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

Ganai

Abdullah

Rashid

et al. 2017

Front. Mol. Neurosci.

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“…In another study, SB939 was shown to have anticancer properties, and was shown to have maximum efficacy in doublet therapy. In addition, pracinostat shows these same results against more therapeutically challenging cancers 7 . SB939 was also cited as a viable treatment drug for acute myeloid leukemia based on the studies discussed above 8 .…”

Section: Introductionmentioning

confidence: 82%

Combining Two Classes of Epigenetic Modifiers and Their Effect on Prostate Cancer Cells

Lodi

Goliadze

Manjili

et al. 2020

Preprint

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The main objective of this experiment was to determine and study the effects of combining two epigenetic modifiers, 5-azacyticidine (5-AzaC) and SB939, on a RM-1 murine prostate cancer cell model. The effectiveness of this combination on prostate cancer cells has not been previously studied. The study was implemented on ex vivo cell models to gain a better understanding of the true effects of the combination therapy on prostate cancer cells. Two variations of the combination therapy were tested in this study, each with different concentrations of SB939 (100nm and 200nm). To determine the effectivity of the combination therapy on prostate cancer cells, three factors were measured: cell proliferation, cancer testis antigen (CTA) expression, and apoptosis rate. To measure cell proliferation, a cell proliferation assay was conducted, and absorption rate was measured through a 450 nm wavelength. CTA expression was measured through a quantitative polymerase chain reaction (quant-PCR). For this study, the expression rates of five CTAs were measured (TEX15, CEP55, CCNA1, P1A, SPA17). Apoptosis rate was measured through an Annexin-V assay, in which two markers, Annexin-V and 7-AAD, were used. We found that SB939 combined with 5-AzaC show highest efficacy compare to each drug alone in terms of inhibiting tumor cell proliferation, as well as inducing tumor cells apoptosis and enhancing tumor cell immunogenicity by the induction of the expression of CTAs. This combination proved to be effective in combating murine prostate cancer cells, and can potentially be effective within in vivo models due to its high toxicity to these cancer cells, and its ability to render prostate cancer more immunogenic.

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“…Among them, Pracinostat 1 is a promising compound, which has been granted breakthrough therapy designation by FDA for the treatment of patients with newly diagnosed acute myelocytic leukemia (AML) who are ≥75 years of age or unfit for intensive chemotherapy(Abaza et al., ; Garcia‐Manero et al., ). Currently, Pracinostat is undergoing phase III clinical trials (Abaza et al., ; Ganai, ; Garcia‐Manero et al., ; Kang et al., ; Novotny‐Diermayr et al., ).…”

Section: Introductionmentioning

confidence: 99%

Minor structural modifications to Pracinostat produce big changes in its biological responses

et al. 2019

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A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5-or 6-position were designed, synthesized, and evaluated as HDAC inhibitors. It was interesting to find that the corresponding derivative 1 with N-hydroxyacrylamide attached at 5-position was a potent HDAC inhibitor while the others at 6-position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates. K E Y W O R D S HDAC inhibitors, histone deacetylases, hydroxamic acids, Pracinostat, synthesisThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance

Cited by 18 publications

References 62 publications

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

Combining Two Classes of Epigenetic Modifiers and Their Effect on Prostate Cancer Cells

Minor structural modifications to Pracinostat produce big changes in its biological responses

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