Third year PhD candidate, Kadir Has University Istanbul
-selective HDAC inhibitors by a combined approach of molecular docking and dynamics studies
Computational studies of biomolecular interaction speed up the process of drug discovery. Here, the fact that HDACs are implicated in the pathogenesis of various cancers, we apply such methodologies towards the design of HDAC inhibitors for cancer therapy.
Abstract: Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas.
Pub.: 22 Jul '17, Pinned: 20 Sep '17
Abstract: Industrialized drug screening campaigns usually deliver hundreds of compounds that are active on a particular pharmaceutical target. In light of high failure rates of drug candidates due to unforeseeable off-target toxicity, the early identification of the most promising compounds with high potential for target selectivity is an urgent need to improve the quality of lead compounds and lower attrition rates in the drug development process. The reliable prediction of the selectivity of active substances for a target protein is a challenging task. A comprehensive study of the binding kinetics, thermodynamics, and selectivity of chemically related ligands of histone deacetylase (HDAC) like amidohydrolase from Pseudomonas aeruginosa (HDAHpa ) reveals one general binding mechanism for all analyzed compounds consisting of a preceding conformational selection step followed by an optional subsequent induced fit. Depending on the chemical structure, the ligands bind to one or two of at least three protein conformations with different rate constants. Although these kinetic and mechanistic differences hamper the predictability of selectivity for the HDAC inhibitors, we demonstrate that the enthalpy-weighted binding constant KdΔH is a useful metric to predict isoform selectivity of inhibitors against HDAC enzymes and relatively robust toward different but related binding mechanisms.
Pub.: 22 Jul '17, Pinned: 20 Sep '17
Abstract: In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC50 of 1.8-2.6 μM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics.
Pub.: 08 Jul '17, Pinned: 20 Sep '17
Abstract: The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency.In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals.Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells.These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed.Clinicaltrials.gov NCT01319383.NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109.
Pub.: 18 Jul '17, Pinned: 20 Sep '17
Abstract: Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatin A (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1 phase accompanied by reduced expression of cyclin D1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637 cells through caspase-3 activation followed by PARP cleavage. The loss of mitochondrial membrane potential (MMP) indicated that TSA induced apoptosis in 5,637 cells through the intrinsic mitochondrial pathway. TSA significantly suppressed Akt activity at 12 h after treatment, suggesting that the apoptosis in the early phase was mediated by Akt inhibition. In addition, the protein level of transcription factor Sp1 was decreased at 24 h after TSA treatment, which likely led to the downregulation of survivin gene expression, and then contributed to the antitumor activity of TSA. Taken together, the present study delineated that TSA-induced growth inhibition and apoptosis in 5,637 cells was associated with pAKT inhibition and MMP loss at the early phase, followed by downregulation of Sp1 and survivin at the late phase of treatment.
Pub.: 18 Jul '17, Pinned: 20 Sep '17
Abstract: Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple-negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an epigenetic therapy to antiestrogen therapy may be an effective approach to targeting resistance pathways in breast cancer, particularly in hormone-positive disease. Agents such as entinostat may have a role in immunogenic modulation. Genetic and pharmacological inhibition studies identified HDAC as a key determinant in the reversal of carcinoma immune escape. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.
Pub.: 19 Jul '17, Pinned: 20 Sep '17
Abstract: Intrinsic and/or acquired resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) commonly occurs in patients with non-small-cell lung cancer (NSCLC). Here, we develop a combined therapy of histone deacetylase inhibition by a novel HDAC inhibitor, YF454A, with erlotinib to overcome EGFR-TKI resistance in NSCLC.The sensitization of erlotinib by YF454A was examined in a panel of EGFR-TKI-resistant NSCLC cell lines in vitro and two different erlotinib-resistant NSCLC xenograft mouse models in vivo. Western blotting and Affymetrix GeneChip expression analysis were further performed to determine underlying mechanisms for the combinatorial effects of erlotinib and YF454A.YF454A and erlotinib showed a strong synergy in the suppression of cell growth by blocking the cell cycle and triggering cell apoptosis in EGFR-TKI-resistant NSCLC cells. The combined treatment led to a significant decrease in tumor growth and tumor weight compared with single agents alone (P<0.05). Mechanistically, this combination therapy dramatically down-regulated the expression of several crucial EGFR-TKI-resistance-related receptor tyrosine kinases, such as Her2, c-Met, IGF1R and AXL, at both the transcriptional and protein levels, and consequently blocked the activation of downstream molecules AKT and ERK. Transcriptomic profiling analysis further revealed that YF-454A and erlotinib synergistically suppressed the cell cycle pathway and decreased the transcription of cell-cycle related genes, such as MSH6 and MCM7.Our preclinical study of YF454A provided a rationale for combining erlotinib with histone deacetylases inhibitor to treat NSCLC with EGFR-TKI resistance.
Pub.: 28 Jul '17, Pinned: 20 Sep '17
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