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Chemical Biology & Drug Design Aug 2019A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5- or 6-position were designed, synthesized, and...
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.
Topics: Benzimidazoles; HeLa Cells; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans
PubMed: 30932330
DOI: 10.1111/cbdd.13527 -
Combinatorial Chemistry & High... 2019Mantle Cell Lymphoma (MCL) is typically an aggressive and rare disease with poor prognosis, therefore new effective therapeutics are urgently needed. Drug repurposing...
AIM AND OBJECTIVE
Mantle Cell Lymphoma (MCL) is typically an aggressive and rare disease with poor prognosis, therefore new effective therapeutics are urgently needed. Drug repurposing for cancer treatment is becoming increasingly more attractive as an alternative approach to discover clinically approved drugs that demonstrate antineoplastic effect. The objective of this study was to screen an approved drug library and identify candidate compounds with an antineoplastic effect in MCL cells using High-Throughput Screening (HTS) technique.
MATERIALS AND METHODS
Using the HTS technique, nearly 3,800 clinically approved drugs and drug candidates were screened in Jeko and Mino MCL cell lines. We also demonstrated the selectivity window of the candidate compounds in six normal cell lines. Further validations were performed in caspase-3/7 apoptosis assay and three-dimensional (3D) multicellular aggregates model using Z138 cell line.
RESULTS
We identified 98 compounds showing >50% inhibition in either MCL cell line screened, they were distributed across eight unique therapeutic categories and have different mechanisms of action (MOA). We selected alisertib, carfilzomib, pracinostat and YM155 for further validation based on their antiproliferative activity in two MCL cell lines, selectivity to normal cell lines, and drug developing stages in terms of clinical research. Alisertib and carfilzomib showed antiproliferative effect on MCL cell with EC50 = 6 nM and >100-fold selectivity to normal cell lines, especially for alisertib which demonstrated >1000-fold selectivity to 5 out of 6 normal cell lines. Pracinostat and YM155 had potency of 11 and 12 nM in MCL cell with >20-fold selectivity to normal cell lines. All four compounds had been tested in caspase-dependent apoptosis assay. We further validated and demonstrated their anti-MCL effect on cell proliferation and (3D) multicellular aggregates model using Z138 cell line.
CONCLUSION
This is the first study to examine such a large library of clinically approved compounds for the identification of novel drug candidates for MCL treatment, the results could be rapidly translated into clinical practice in patients with MCL.
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Drug Discovery; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; High-Throughput Screening Assays; Humans; Lymphoma, Mantle-Cell; Small Molecule Libraries
PubMed: 31526347
DOI: 10.2174/1386207322666190916120128 -
Leukemia Research Aug 2014
Topics: Animals; Antineoplastic Agents; Benzimidazoles; Drug Discovery; Epigenesis, Genetic; Flavonoids; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Orphan Drug Production; Piperidines; Protein Kinase Inhibitors; Pteridines; Terminology as Topic
PubMed: 24996975
DOI: 10.1016/j.leukres.2014.06.007 -
Journal of Biomolecular Structure &... Mar 2022Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression....
Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme's stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme's active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research.Communicated by Ramaswamy H. Sarma.
Topics: Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Molecular Dynamics Simulation; Neoplasms
PubMed: 33131428
DOI: 10.1080/07391102.2020.1838328 -
Bioinformatics and Biology Insights 2022Differential expressions of certain genes during tumorigenesis may serve to identify novel manageable targets in the clinic. In this work with an integrated...
Differential expressions of certain genes during tumorigenesis may serve to identify novel manageable targets in the clinic. In this work with an integrated bioinformatics approach, we analyzed public microarray datasets from Gene Expression Omnibus (GEO) to explore the key differentially expressed genes (DEGs) in non-small cell lung cancer (NSCLC). We identified a total of 984 common DEGs in 252 healthy and 254 NSCLC gene expression samples. The top 10 DEGs as a result of pathway enrichment and protein-protein interaction analysis were further investigated for their prognostic performances. Among these, we identified high expressions of , , , , and genes that were associated with significantly poorer overall survival in NSCLC patients. On the contrary, high mRNA expressions of , , , and were associated with a significantly better prognosis. Furthermore, our drug target analysis for these hub genes suggests a potential use of Trichostatin A, Pracinostat, TGX-221, PHA-793887, AG-879, and IMD0354 antineoplastic agents to reverse the expression of these DEGs in NSCLC patients.
PubMed: 35422618
DOI: 10.1177/11779322221088796 -
PLoS Neglected Tropical Diseases Sep 2020Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba...
Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.
Topics: Acanthamoeba; Amebiasis; Amebicides; Balamuthia mandrillaris; Databases, Pharmaceutical; Drug Repositioning; High-Throughput Screening Assays; Naegleria fowleri; Neglected Diseases; Small Molecule Libraries
PubMed: 32970675
DOI: 10.1371/journal.pntd.0008353 -
Cancer Discovery Nov 2018, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration...
, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad deletion in mouse neuroendocrine cells cooperated with loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that loss results in reduced expression of tight junction and cell adhesion genes, including , across neuroendocrine tumor types, whereas suppression of promoted transformation in SCLC. and other adhesion genes exhibited reduced histone acetylation with inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of -deficient SCLC exhibited exceptional responses to Pracinostat Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy. Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in -deleted tumors. These data provide a rationale for selectively treating -mutant SCLC with HDAC inhibitors. .
Topics: Acetylation; Animals; CREB-Binding Protein; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lung Neoplasms; Mice; Mice, Knockout; Mutation; Retinoblastoma Protein; Small Cell Lung Carcinoma; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 30181244
DOI: 10.1158/2159-8290.CD-18-0385 -
Nature Genetics Jul 2017Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene...
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
Topics: Alternative Splicing; Animals; Benzimidazoles; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Death-Associated Protein Kinases; Epigenetic Repression; Exons; Female; Gene Expression Profiling; Gene Silencing; Histone Code; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Introns; Mice; Mice, Nude; RNA Interference; Recombinant Fusion Proteins; Terminal Repeat Sequences; Transcription Initiation Site; Vorinostat
PubMed: 28604729
DOI: 10.1038/ng.3889 -
International Journal of Molecular... Mar 2019Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical...
Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders.
Topics: Benzimidazoles; Benzofurans; Brain-Derived Neurotrophic Factor; Cells, Cultured; HEK293 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neural Stem Cells; Neuronal Outgrowth
PubMed: 30841499
DOI: 10.3390/ijms20051109 -
International Immunopharmacology Jan 2017Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti-fibrotic agents is urgently needed....
Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti-fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti-fibrosis drugs. Therefore, more potentially relevant anti-renal fibrosis HDAC inhibitors are needed. We initially found that non-cytotoxic concentrations of SB939 (pracinostat) had strong anti-fibrotic activity, drastically decreasing TGF-β1-induced alpha smooth muscle actin (α-SMA) expression in the NRK renal fibroblast cell line. Similar anti-fibrotic activity of SB939 on epithelial-to-mesenchymal transition (EMT) was confirmed using the HK-2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad-independent TGF-β signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti-fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of α-SMA and tissue injury. Inflammatory and pro-fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis.
Topics: Animals; Anti-Inflammatory Agents; Benzimidazoles; Cell Differentiation; Cell Line; Disease Models, Animal; Fibrosis; Histone Deacetylase Inhibitors; Humans; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Myofibroblasts; Rats; Signal Transduction; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 27855304
DOI: 10.1016/j.intimp.2016.11.008