The Experts below are selected from a list of 1992 Experts worldwide ranked by ideXlab platform
Sk Abdul Amin - One of the best experts on this subject based on the ideXlab platform.
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structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi qsar modeling study
Journal of Biomolecular Structure & Dynamics, 2020Co-Authors: Suvankar Banerjee, Nilanjan Adhikari, Sk Abdul AminAbstract:AbstractHistone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disea...
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histone deacetylase 8 HDAC8 and its inhibitors with selectivity to other isoforms an overview
European Journal of Medicinal Chemistry, 2019Co-Authors: Suvankar Banerjee, Nilanjan Adhikari, Sk Abdul AminAbstract:Abstract The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disorders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic activity.
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selective and nonselective HDAC8 inhibitors a therapeutic patent review
Pharmaceutical patent analyst, 2018Co-Authors: Nilanjan Adhikari, Sk Abdul AminAbstract:Histone deacetylase 8 (HDAC8) is one of the attractive therapeutic anticancer targets. HDAC8 has been overexpressed in a variety of human cancers. Therefore, HDAC8 inhibitors offer beneficial effects in the treatment of solid and hematological tumors. Different HDAC inhibitors entered into different phases of clinical studies. However, selectivity towards specific HDAC8 enzyme is still demanding. In this patent review, a number of patented selective and nonselective HDAC8 inhibitors along with their implication as anticancer agents have been discussed in details. Molecules should possess modified fish-like structural arrangement to impart potency and selectivity towards HDAC8. This comprehensive patent analysis will surely provide newer aspects of designing selective HDAC8 inhibitors targeted to anticancer therapy in future.
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structure activity relationships of HDAC8 inhibitors non hydroxamates as anticancer agents
Pharmacological Research, 2018Co-Authors: Sk Abdul Amin, Nilanjan AdhikariAbstract:Abstract Histone deacetylase inhibitors (HDACIs) have a paramount importance in the acetylation process of histone and non-histone proteins that are crucial players in the cellular epigenetic modifications. HDACIs exert effective antiproliferation through DNA repairing, cell cycle arrest, apoptosis induction and alteration of genetic expression. HDAC8 is one of the crucial HDACs, affects the epigenetic gene silencing process and cancer progression. Hence, HDAC8 is one of the key cancer targets among class I HDACs that may be effectively blocked as a benchmark therapy to combat malignancy. In the current review, a special emphasis has been given for the non-hydroxamate type of HDAC8 inhibitors. It may provide some fruitful structural information to design newer better active candidates to fight against target specific malignancies in future.
Jing Qi - One of the best experts on this subject based on the ideXlab platform.
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HDAC8 Promotes MLL-Rearranged Acute Myeloid Leukemia By Inhibiting p53 Acetylation
Blood, 2019Co-Authors: Dijiong Wu, Man Li, Lianjun Zhang, Jing Qi, Chun-wei David Chen, Xin He, Haojie Dong, Ling LiAbstract:Chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene at the 11q23 locus are found in a subset of acute myeloid leukemia (AML) generally associated with intermediate to poor prognosis. MLL-AF9 resulting from t(9;11)(p22;q23) is the most common in MLL-rearranged (MLL-r) AML. Chemotherapy is the current standard of care for AML and the overall 5-year survival rate is only 25%. We previously reported that HDAC8 functions to control p53 activity in hematopoietic stem cells via deacetylation of p53 protein (Hua et al, Blood 2017). Here, we investigated the contribution of HDAC8 in MLL-r AML pathogenesis and maintenance. We have previously generated a conditional HDAC8 floxed (f) allele and combined with Mx1-Cre (Mx1-Cre/HDAC8f/f(y)) to generate HDAC8△/△ mice upon induction with poly (I:C). To examine the role of HDAC8 in MLL-AF9-AML, we transduced HDAC8△/△ or control LSK (Lin-Sca1+cKit+) with a MSCV-ires-GFP (MIG)-MLL-AF9 (MA9) vector and sorted GFP+ cells for CFC assay. HDAC8△/△/MA9 cells generated significantly less CFC colonies compared to control, suggesting that HDAC8 promotes MA9 clonogenic activity. To assess their leukemogenic potential in vivo, we transplanted GFP+ control MA9 or HDAC8△/△/MA9 cells (5x103-104) into sublethally irradiated (6 Gy) wild-type (WT) recipients. All MA9 recipients (n=4) developed lethal AML with a median survival of 69 days while none of the HDAC8△/△/MA9 recipients (n=4) developed AML up to 4 months. To examine the contribution of HDAC8 in established AML, we transduced LSK from uninduced HDAC8f/f(y)/Mx1-Cre mice with MIG-MA9 and transplanted into WT recipients. Upon development of moribund leukemia, AML cells (5x 103) were transplanted into a cohort of recipients (n=16), which were treated with poly (I:C) (n=8; 14 mg/kg/dose) or PBS every other day for 2 weeks starting at day 10 (5-10% GFP+ in blood). Mice induced with poly (I:C) to delete HDAC8 showed dramatically lower white blood count [9.0 (103 /ul) vs. 109.7 (103 /ul); n=8, P<0.05] and lower AML burden (GFP+) in peripheral blood (9.3% vs 42.3%; n=8, P<0.05) at 3 weeks. Prolonged survival was observed in poly (I:C) treated mice compared to control (median survival 36 days vs 27 days, n=8, P<0.01). These results indicate that HDAC8 deletion impairs AML progression. Thus, we examined the effects of HDAC8-selective inhibitor (HDAC8i) on MA9 AML cell proliferation and survival. Treatment of MA9 AML cells with HDAC8i (22d) led to dose-dependent inhibition of cell survival (IC50 = 4.724 - 8.453 mM) and increased apoptosis (10 mM, 48 h) compared to vehicle treated control (40% vs. 7%). HDAC8i treatment significantly enhanced p53 acetylation, and upregulated p53 target genes, Gadd45d (fold change = 3.2; p< 0.01), Puma (fold change = 5.7; p< 0.01), Mdm2 (fold change = 3.0; p< 0.01) and Cdkn1a (fold change = 3.6; p< 0.01). To assess the effects on AML growth and leukemia-initiating capacity in vivo, we transplanted MA9 AML cells treated with HDAC8i (1 x 105, 2.5x105) or vehicle (2.5x105) into sublethally irradiated WT recipients (n=8-11). We observed significantly (p<0.0001) reduced GFP+ AML burden in recipients of HDAC8i-treated cells (both 1x105 & 2 x105) and significantly (p<0.0001) improved survival. Secondary transplantation of AML cells from HDAC8i- or vehicle-treated (2 x105) recipients revealed significantly improved survival in HDAC8i-treated group (22d 105 days n=4 vs. vehicle 33 days n=5; p< 0.01). These results indicate that HDAC8 inhibition enhanced elimination of MA9 AML cells and leukemia-initiating cells. We further evaluated the effect of HDAC8i in human AML cell lines and primary MLL-r AML patient cells. HDAC8i treatment increased p53 acetylation and enhanced p53-dependent apoptosis in MOLM-13 AML cells (22d: 50.8% vs. vehicle: 11.89%). Knock-down of p53 rescued the apoptosis induced by HDAC8i, indicating that HDAC8i induced apoptosis is mediated by p53. Similarly, HDAC8i (22d) treatment significantly increased apoptosis accompanied by elevated levels of p53 acetylation and p53 target gene expression in MLL-r AML CD34+ cells compared to normal (NL) CD34+ cells. Thus, HDAC8 inhibition targets human MLL-r AML cells and AML CD34+ cells by restoring p53 acetylation and inducing apoptosis. In conclusion, this study reveals a critical role of HDAC8 in promoting initiation and maintenance of MLL-AF9 AML and highlights HDAC8 inhibition as a promising approach to target MLL-r AML. Disclosures No relevant conflicts of interest to declare.
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HDAC8 regulates long term hematopoietic stem cell quiescence and maintenance
Blood, 2016Co-Authors: Jing Qi, Ling Li, Emily Carnahan, Guido MarcucciAbstract:Long-term (LT) hematopoietic stem cells (HSC) are responsible for life-long production of mature blood cells of all lineages through tightly concerted cell fate decisions including quiescence, self-renewal, differentiation and apoptosis. Histone deacetylase 8 (HDAC8) is a member of class I HDAC enzymes that remove acetyl moieties from lysine residues on histones and a variety of non-histone proteins. Specifically, HDAC8 has been shown to modulate the acetylation cycle of cohesin complex protein SMC3. Loss-of-function mutations in HDAC8, located on the X chromosome q13, have been found in patients with Cornelia de Lange Syndrome (CdLS) and those with CdLS-like features. These HDAC8 mutations are associated with severely skewed X-inactivation (100% wild type allele) in the peripheral blood of female patients, possibly due to selection against the mutant alleles. However, the expression and function of HDAC8 in normal HSCs and hematopoiesis remain unknown. In this study, we show that HDAC8 is highly expressed in the phenotypic LT-HSC (Lin-cKit+Sca1+CD150+CD48-) population in adult mice. To determine the function of HDAC8 in adult hematopoiesis, we generated conditional HDAC8 deficient mice using the Mx1-Cre and a floxed HDAC8 allele (Mx1-Cre/HDAC8f/f(y)) andconfirmed that HDAC8 is successfully deleted by polyinosinic-polycytidylic acid [poly (I:C)] treatment. Phenotypic analysis of HDAC8 deficient mice showed increased LT-HSC population compared to similarly treated control mice. However, largely normal steady state hematopoietic profile was found in HDAC8 deficient mice at 6 weeks and 1 year after induction. To further track HDAC8-deleted cells, we generated Cre/HDAC8f/f(y) mice with a dual fluorescence Rosa26mT/mG (mT/mG) Cre reporter allele, which expresses dTomato prior to Cre induction and becomes GFP+ after Cre-mediated recombination. We assessed hematopoietic repopulation by transplanting bone marrow cells from Cre/HDAC8f/f(y)/mTmG+mice (2 x 105) together with wild type support cells (2 x 105) into lethally irradiated CD45.1+ congenic recipients. HDAC8 deletion was induced by treating the recipients with 7 does (14 m▢g/kg/dose) of poly (I:C). We found that HDAC8 deletion did not affect CD45.2+ or GFP+ donor-derived overall engraftment or lineage repopulation up to 16 weeks. There was also no change in the frequency or number of GFP+ donor-derived phenotypic LT-HSCs in the bone marrow. Serial transplantation was performed to further assess long-term repopulating activity of HSCs. HDAC8 deficient cells were significantly (p=0.019; n=3) compromised in multi-lineage repopulation in secondary transplant recipients. Except a modest reduction in Pre-GM, there was no change in the overall composition of HDAC8 deficient CD45.2+-derived populations. Upon tertiary transplantation, no donor engraftment was observed for HDAC8 deficient cells (0 out of 4) compared to 50% positive engraftment in control group (4 out of 8). These results indicate that HDAC8 is crucial for maintaining long-term serial-repopulating activity over time. Cell cycle analysis revealed that HDAC8 deficient LT-HSCs display reduced quiescence and increased cycling, consistent with the increased number of phenotypic LT-HSC seen in HDAC8 deleted mice. Therefore, we further tested the sensitivity of HDAC8 deficient mice to serial ablation with 5-fluorouracil (5FU), an S phase-specific cytotoxic chemotherapeutic agent. Impaired hematopoietic recovery and increased lethality (p 100 cells). Analysis of p53 activation, cell cycle regulators and DNA dmage response are ongoing. Collectively, our study indicates that HDAC8 plays a pivotal role in LT-HSC quiescence and maintenance. Disclosures No relevant conflicts of interest to declare.
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HDAC8 inhibition specifically targets inv 16 acute myeloid leukemic stem cells by restoring p53 acetylation
Cell Stem Cell, 2015Co-Authors: Jing Qi, Ling Li, Guido Marcucci, Sandeep Singh, Shi Wei Chao, Yinwei Ho, Tinisha Mcdonald, Ravi Bhatia, Wei Jan Huang, Chungi ChangAbstract:Summary Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16) + AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16) + AML CD34 + cells, while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates an HDAC8-mediated p53-inactivating mechanism promoting LSC activity and highlights HDAC8 inhibition as a promising approach to selectively target inv(16) + LSCs.
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cbfβ smmhc inactivates p53 tumor suppressor through aberrant protein interaction and recruitment of HDAC8
Blood, 2012Co-Authors: Jing Qi, Sandeep Singh, Hieu Vu, Sriram BalasubramanianAbstract:Abstract 772 Chromosomal inversion inv(16)(p13.1q22) is found in approximately 12% of acute myeloid leukemia (AML) patients, and leads to the fusion of the transcription factor gene CBFb and the MYH11 gene, and encodes a fusion protein CBFβ-SMMHC. Previous studies revealed that CBFβ-SMMHC is a dominant inhibitor of core-binding factor (CBF) function, and impairs hematopoietic differentiation. Expression of CBFβ-SMMHC predisposes for leukemia transformation, however, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC remains elusive. The tumor suppressor p53 is considered the master genomic guardian that is frequently mutated in a wide variety of tumors but is rarely mutated in inv(16) AML. Thus, we examined whether CBFβ-SMMHC fusion protein might impair p53 function. We found that p53 acetylation (Ac-p53) level was reduced in the presence of CBFβ-SMMHC fusion protein in the myeloid progenitor 32D cell line as well as in primary pre-leukemic bone marrow progenitor cells isolated from our conditional Cbfb-MYH11 knock-in ( Cbfb 56M/ + / Mx1-Cre) mice (Kuo et al, Cancer Cell 2006, 9:1,57-68). We assessed the effect of CBFβ-SMMHC on p53 transcriptional activity by quantitative RT-PCR analysis of p53 target genes including TP53 and p21 Cdkn1a, Mdm2, Bid, Bax, Stag1, LincRNA-p21, Gadd45b in 32D cells. The result showed that expression of these p53 target genes are reduced in the presence of CBFβ-SMMHC fusion protein, consistent with the impaired Ac-p53 by CBFβ-SMMHC. To understand how CBFβ-SMMHC impairs p53 function, we tested whether CBFβ-SMMHC fusion protein might interact with the p53 protein by co-immunoprecipitation (co-IP) assays. We found that CBFβ-SMMHC fusion protein interacts with p53 both in 32D cells and primary bone marrow cells. Although CBFβ-SMMHC fusion protein is detected both in the nucleus and the cytoplasm, the complex with p53 is present exclusively in the nucleus. It has been reported that CBFβ-SMMHC interacts with histone deacetylase 8 (HDAC8) through the C-terminal SMMHC region. Therefore, we assessed the interaction between CBFβ-SMMHC, p53 and HDAC8 in 32D cell line by co-IP and sequential co-IP. We were able to detect a multimeric protein complex containing CBFβ-SMMHC, p53, and HDAC8. To access whether HDAC8 contributes to the deacetylation of p53, we used two independent small-hairpin (sh)-RNA to knock-down HDAC8 in 32D-CBFβ-SMMHC cells. HDAC8 knock-down led to robust increase in Ac-p53 levels while total p53 levels were modestly stabilized. To test whether this effect is dependent on the deacetylase function of HDAC8, we used HDAC8 selective pharmacological inhibitors (HDAC8i including PCI-34051 and PCI-48012) directed against its catalytic sites (Balasubramanian et al Leukemia 2008, 22:5,1026-34). Treatment with HDAC8i remarkably increased Ac-p53 in both control and CBFβ-SMMHC cells. Since p53 protein levels were also increased upon HDAC8i treatment, we included Mdm2 inhibitor Nutlin-3 to stabilize p53. HDAC8i treatment alone or in combination with Nutlin-3 was able to enhance Ac-p53 compared to Nutlin-3 treatment, confirming its effect in restoring p53 acetylation. Collectively, our study shows that the CBFβ-SMMHC fusion protein forms an aberrant complex with p53 and HDAC8, leading to the aberrant deacetylation and impaired activity of p53. In addition, this deacetylation of p53 conferred by CBFβ-SMMHC is mediated by HDAC8. Our study reveals a novel leukemogenic mechanism in which CBFβ-SMMHC disrupts p53 activation through aberrant protein-protein interaction and recruitment of HDAC8. Disclosures: No relevant conflicts of interest to declare.
Joseph J Buggy - One of the best experts on this subject based on the ideXlab platform.
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the histone deacetylase 8 HDAC8 selective inhibitor pci 34051 decreases interleukin 1 beta secretion in vitro and reduces inflammation in vivo
Blood, 2008Co-Authors: Sriram Balasubramanian, Susanne M Steggerda, Mint Sirisawad, Marshall T Schreeder, Luke Doiron, Joseph J BuggyAbstract:Inhibitors of histone deacetylases (HDACs) which are currently in clinical testing for treating various cancers typically inhibit multiple isoforms of the 11-member HDAC family. We have developed an isoform-selective HDAC inhibitor, PCI-34051, that inhibits HDAC8 with a Ki of 10 nM and greater than 200-fold selectivity over other HDAC isoforms (Balasubramanian et al. (2008) Leukemia,22:1026–34). We have shown that PCI-34051 selectively induced apoptosis in cell lines derived from T-cell lymphomas and leukemias, but not in other tumor or normal cell types. Here we show that it potently inhibits the secretion of the pro-inflammatory cytokine interleukin-1 beta (IL-1b) in lipopolysaccharide (LPS)-stimulated peripheral mononuclear blood cells (PBMC) and isolated monocytes. PCI-34051 inhibited IL-1b secretion (by 80% compared to control) from LPS-stimulated human PBMC with an IC50 of 0.6 uM, which is much lower than the growth inhibitory concentrations of 2.4–4 uM required in T-cell lymphomas. We found that PCI-34051 also inhibited the secretion of interleukin-18 (IL-18) to a similar extent as IL-1b, but secretion of other pro-inflammatory cytokines, including MIP-1b, MCP-1, TNFa, and IL-6, was inhibited to a smaller extent. Interestingly, IL-18, like IL-1b, is synthesized without a signal peptide, and also utilizes the same non-classical endosomal secretory pathway as IL-1b including cleavage of the pro-form by caspase-1. Thus, we theorized that the modulatory effect of PCI-34051 is likely to involve modulation of the post-translational secretory process. In accordance, we found that the IL-1b mRNA levels were reduced by only 20% compared to control, but the intracellular protein levels of the pro-form was increased by >50% in primary monocytes after treatment with PCI-34051, indicating that the mechanism was due to inhibition of the processing from the pro- to the mature form of the cytokine. We showed that this was not due to a direct inhibition of caspase-1 or TACE (TNF-alpha converting enzyme), but is likely due to an as-yet unidentified substrate of HDAC8. In vivo, PCI-34051 inhibited ear swelling induced by oxazolone in a model of contact hypersensitivity in mice, and we showed that this was accompanied by a reduction in IL-1b at both the protein and mRNA levels. Based on this result, we examined the effect of PCI-34051 on IL-1b secretion in human keratinocytes, as well as in PBMC from psoriasis patients, and found that it could reduce IL-1b secretion in both. We found that PCI-34051 decreased IL-1b by 60% in LPS-stimulated PBMC from rheumatoid arthritis (RA) patients, but the pan-HDAC inhibitors which were only weakly inhibitory to HDAC8 did not have this effect, indicating a specific role for HDAC8 in the secretory process. Finally, we found that in unstimulated PBMC from RA patients that had basal production of IL-1b that this could be decreased by 90% by treatment with PCI-34051. Taken together, these findings indicate that PCI-34051 is an active drug that could be useful for the treatment of T-cell lymphoma as well as for autoinflammatory diseases such as RA and psoriasis.
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structural snapshots of human HDAC8 provide insights into the class i histone deacetylases
Structure, 2004Co-Authors: John R Somoza, Robert J Skene, Bradley A Katz, Joseph D Ho, Andy Jennings, Christine Luong, Andrew S Arvai, Joseph J Buggy, Jie Tang, B C SangAbstract:Abstract Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
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cloning and characterization of a novel human histone deacetylase HDAC8
Biochemical Journal, 2000Co-Authors: Joseph J Buggy, Mindy L Sideris, Donald D Lorimer, Brian Mcintosh, James M ClarkAbstract:Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597–600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815–818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811–814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDAC8 to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2–Xq21.3. These results confirm HDAC8 as a new member of the HDAC family.
Nilanjan Adhikari - One of the best experts on this subject based on the ideXlab platform.
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structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi qsar modeling study
Journal of Biomolecular Structure & Dynamics, 2020Co-Authors: Suvankar Banerjee, Nilanjan Adhikari, Sk Abdul AminAbstract:AbstractHistone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disea...
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histone deacetylase 8 HDAC8 and its inhibitors with selectivity to other isoforms an overview
European Journal of Medicinal Chemistry, 2019Co-Authors: Suvankar Banerjee, Nilanjan Adhikari, Sk Abdul AminAbstract:Abstract The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disorders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic activity.
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selective and nonselective HDAC8 inhibitors a therapeutic patent review
Pharmaceutical patent analyst, 2018Co-Authors: Nilanjan Adhikari, Sk Abdul AminAbstract:Histone deacetylase 8 (HDAC8) is one of the attractive therapeutic anticancer targets. HDAC8 has been overexpressed in a variety of human cancers. Therefore, HDAC8 inhibitors offer beneficial effects in the treatment of solid and hematological tumors. Different HDAC inhibitors entered into different phases of clinical studies. However, selectivity towards specific HDAC8 enzyme is still demanding. In this patent review, a number of patented selective and nonselective HDAC8 inhibitors along with their implication as anticancer agents have been discussed in details. Molecules should possess modified fish-like structural arrangement to impart potency and selectivity towards HDAC8. This comprehensive patent analysis will surely provide newer aspects of designing selective HDAC8 inhibitors targeted to anticancer therapy in future.
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structure activity relationships of HDAC8 inhibitors non hydroxamates as anticancer agents
Pharmacological Research, 2018Co-Authors: Sk Abdul Amin, Nilanjan AdhikariAbstract:Abstract Histone deacetylase inhibitors (HDACIs) have a paramount importance in the acetylation process of histone and non-histone proteins that are crucial players in the cellular epigenetic modifications. HDACIs exert effective antiproliferation through DNA repairing, cell cycle arrest, apoptosis induction and alteration of genetic expression. HDAC8 is one of the crucial HDACs, affects the epigenetic gene silencing process and cancer progression. Hence, HDAC8 is one of the key cancer targets among class I HDACs that may be effectively blocked as a benchmark therapy to combat malignancy. In the current review, a special emphasis has been given for the non-hydroxamate type of HDAC8 inhibitors. It may provide some fruitful structural information to design newer better active candidates to fight against target specific malignancies in future.
Raphael E Pollock - One of the best experts on this subject based on the ideXlab platform.
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The Role and Therapeutic Implication of HDAC8 in Neuroblastoma
Journal of Headache & Pain Management, 2020Co-Authors: Gonzalo Lopez, Raphael E PollockAbstract:Neuroblastoma lineage arises from a neural crest origin and is a typically common tumor among the pediatric population. Survival rate for this disease has improved over the years, however, patients with MYCN amplification correlate with a poor prognosis, warranting improved therapies. The utility and efficacy of pan-HDAC inhibitors for the treatment for various solid tumors has increased with promising results. Isoform-specific HDAC inhibitors have been developed to improve the therapeutic window and reduce side effects. The role of isoform-specific HDAC inhibitors, namely HDAC8 inhibitors, has recently been investigated in numerous tumor histologies, including neuroblastoma, among other neural crest-derived tumors. Long term pan-HDAC inhibition has been demonstrated to induce differentiation and regression to a benign-like phenotype in neuroblastoma in vivo. HDAC8 inhibition has been shown to inhibit growth and induce differentiation in neuroblastoma cells. The role of HDAC8 inhibition on neuroblastoma and regression of the disease merits further investigation.
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Evaluating the Effect of HDAC8 Inhibition in Malignant Peripheral Nerve Sheath Tumors
Methods of Molecular Biology, 2016Co-Authors: Gonzalo Lopez, Raphael E PollockAbstract:Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive disease with a dismal prognosis. The disease can occur sporadically or in patients with inherited neurofibromatosis (NF-1). MPNST is typically resistant to therapeutic intervention. Hence, the need for improved therapies is warranted. Several broad spectrum histone deacetylase (HDAC) inhibitors have a high affinity for class I HDAC isoforms. Inhibition of multiple HDAC isoforms often results in undesirable side effects, while inhibiting a single isoform could possibly improve the therapeutic window and limit toxicity. Recently, HDAC8 inhibitors have been developed and in initial preclinical studies, they demonstrate anticancer efficacy. Little is known about the role of HDAC8 in MPNST. We recently revealed an anticancer effect of HDAC8 inhibition in human and murine MPNST models. The goal of our previous study was to determine the potential therapeutic efficacy of HDAC8 inhibition in MPNST. In this chapter, we briefly describe the methods for determining the role of pharmacological HDAC inhibition in MPNST.
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HDAC8 a potential therapeutic target for the treatment of malignant peripheral nerve sheath tumors mpnst
PLOS ONE, 2015Co-Authors: Gonzalo Lopez, Kate Lynn J Bill, Danielle Braggio, Dylan Constantino, Bethany C Prudner, Abeba Zewdu, Kara Batte, Raphael E PollockAbstract:Introduction HDAC isoform-specific inhibitors may improve the therapeutic window while limiting toxicities. Developing inhibitors against class I isoforms poses difficulties as they share high homology among their catalytic sites; however, HDAC8 is structurally unique compared to other class I isoforms. HDAC8 inhibitors are novel compounds and have affinity for class I HDAC isoforms demonstrating anti-cancer effects; little is known about their activity in malignant peripheral nerve sheath tumors (MPNST). Recently, we demonstrated anti-MPNST efficacy of HDAC8i in human and murine-derived MPNST pre-clinical models; we now seek to consider the potential therapeutic inhibition of HDAC8 in MPNST. Methods Four Human MPNST cell lines, a murine-derived MPNST cell line, and two HDAC8 inhibitors (PCI-34051, PCI-48012; Pharmacyclics, Inc. Sunnyvale, CA) were studied. Proliferation was determined using MTS and clonogenic assays. Effects on cell cycle were determined via PI FACS analysis; effects on apoptosis were determined using Annexin V-PI FACS analysis and cleaved caspase 3 expression. In vivo growth effects of HDAC8i were evaluated using MPNST xenograft models. 2D gel electrophoresis and mass spectrometry were used to identify potential HDAC8 deacetylation substrates. Results HDAC8i induced cell growth inhibition and marked S-phase cell cycle arrest in human and murine-derived MPNST cells. Relative to control, HDAC8i induced apoptosis in both human and murine-derived MPNST cells. HDAC8i exhibited significant effects on MPNST xenograft growth (p=0.001) and tumor weight (p=0.02). Four potential HDAC8 substrate targets were identified using a proteomic approach: PARK7, HMGB1, PGAM1, PRDX6. Conclusions MPNST is an aggressive sarcoma that is notoriously therapy-resistant, hence the urgent need for improved anti-MPNST therapies. HDAC8 inhibition may be useful for MPNST by improving efficacy while limiting toxicities as compared to pan-HDACis.
