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Journal of Enzyme Inhibition and... Dec 2024A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor,...
Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound , containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC = 16 nM and 1.03 µM, respectively). Compound also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC, 4.9 nM). Moreover, inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers , was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
Topics: Mice; Animals; Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Histone Deacetylase Inhibitors; Mice, Nude; Lung Neoplasms; Cell Proliferation; Protein Kinase Inhibitors; Antineoplastic Agents; Cell Line, Tumor
PubMed: 38465731
DOI: 10.1080/14756366.2024.2318645 -
Cancer Cell International Apr 2013The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to...
Activity of histone deacetylase inhibitors and an Aurora kinase inhibitor in BCR-ABL-expressing leukemia cells: Combination of HDAC and Aurora inhibitors in BCR-ABL-expressing cells.
BACKGROUND
The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to imatinib mediated by mutations in the BCR-ABL domain has become a major problem in the treatment of these patients.
METHODS
In the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells.
RESULTS
We found the HDAC inhibitors vorinostat and/or pracinostat (SB939) induced apoptosis in BCR-ABL-expressing cells. Additionally, HDAC inhibitors reduced levels of Aurora A and B protein. An Aurora kinase inhibitor, tozasertib (VX-680), inhibited growth, promoted pro-apoptotic activity, reduced the phosphorylation of BCR-ABL and Crk-L, and activated caspase-3 and poly (ADP-ribose) polymerase (PARP) in BCR-ABL-positive cells. Moreover, after treatment with tozasertib, HDAC protein expression was decreased. Combination of vorinostat or pracinostat with tozasertib had a synergistic inhibitory effect on the proliferation of T315I cells. Phosphorylation of Crk-L decreased, and PARP activation increased after treatment with vorinostat or pracinostat and tozasertib. Moreover, combination of vorinostat or pracinostat and tozasertib significantly increased the extent of apoptosis in primary chronic myeloid leukemia cells.
CONCLUSIONS
This study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.
PubMed: 23556431
DOI: 10.1186/1475-2867-13-32 -
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 -
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 -
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 -
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 -
Antimicrobial Agents and Chemotherapy Jul 2012Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other...
Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC(50)], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC(50), ~150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.
Topics: Animals; Antimalarials; Antineoplastic Agents; Benzimidazoles; Cerebrum; Histone Deacetylase Inhibitors; Malaria; Mice; Plasmodium falciparum
PubMed: 22508312
DOI: 10.1128/AAC.00030-12 -
PloS One 2017Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI...
Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.
Topics: Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Benzimidazoles; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Deletion; Histone Deacetylase Inhibitors; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; RNA Splicing
PubMed: 28301600
DOI: 10.1371/journal.pone.0174107 -
Annals of Oncology : Official Journal... Nov 2011The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel...
BACKGROUND
The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.
PATIENTS AND METHODS
Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs).
RESULTS
Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose.
CONCLUSIONS
SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.
Topics: Administration, Oral; Adult; Aged; Benzimidazoles; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Male; Middle Aged; Neoplasms
PubMed: 21385886
DOI: 10.1093/annonc/mdq784 -
British Journal of Cancer Mar 2011SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939...
BACKGROUND
SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours.
METHODS
Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels.
RESULTS
In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response.
CONCLUSIONS
SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Drug Administration Schedule; Fatigue; Female; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Nausea; Neoplasms; Vomiting
PubMed: 21285985
DOI: 10.1038/bjc.2011.13