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1.
Toxicol Lett ; 320: 19-27, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778773

RESUMO

The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 ß-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.


Assuntos
Anilidas/farmacologia , Benzoquinonas/farmacologia , Dexametasona/toxicidade , Glucocorticoides/toxicidade , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Acetilação , Animais , Linhagem Celular , Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Ratos Sprague-Dawley , Via Secretória , Técnicas de Cultura de Tecidos
2.
Eur J Med Chem ; 187: 111950, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865013

RESUMO

Histone deacetylase 6 (HDAC6) has gained popular attention for its wide participation in various pathological process recently. In this paper, a series of novel derivatives containing 2, 5-diketopiperazine (DKP) skeleton were developed as potent selective HDAC6 inhibitors (sHDAC6is). Most of these compounds exhibited low nanomolar IC50 values toward HDAC6, and the best compound was 21b (IC50 = 0.73 nM) which had 144-10941-fold selectivity over other HDAC isoforms. Western blot assay further validated these compounds to be sHDAC6is. Molecular simulation of 21b was conducted to rationalize the high binding affinity for HDAC6. In the cytotoxicity experiment, 18a, 18b and 18d gave superior or comparable influence on the growth of two multiple myeloma cells U266 and RPMI-8226 compared to ACY-1215. Moreover, the combination of 18a and adriamycin showed synergistic effect against non-small cell lung cancer cell A549. 18a and 18b also demonstrated appropriate drug metabolism in human liver microsome (HLM).


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Expert Opin Ther Pat ; 30(2): 121-136, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865813

RESUMO

Introduction: Histone deacetylase 6 (HDAC6) is unique in comparison with other zinc-dependent HDAC family members. An increasing amount of evidence from clinical and preclinical research demonstrates the potential of HDAC6 inhibition as an effective therapeutic approach for the treatment of cancer, autoimmune diseases, as well as neurological disorders. The recently disclosed crystal structures of HDAC6-ligand complexes offer further means for achieving pharmacophore refinement, thus further accelerating the pace of HDAC6 inhibitor discovery in the last few years.Area covered: This review summarizes the latest clinical status of HDAC6 inhibitors, discusses pharmacological applications of selective HDAC6 inhibitors in neurodegenerative diseases, and describes the patent applications dealing with HDAC6 inhibitors from 2014-2019 that have not been reported in research articles.Expert opinion: Phenylhydroxamate has proven a very useful scaffold in the discovery of potent and selective HDAC6 inhibitors. However, weaknesses of the hydroxamate function such as metabolic instability and mutagenic potential limit its application in the neurological field, where long-term administration is required. The recent invention of oxadiazole-based ligands by pharmaceutical companies may provide a new opportunity to optimize the druglike properties of HDAC6 inhibitors for the treatment of neurodegenerative diseases.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Desenvolvimento de Medicamentos , Humanos , Doenças Neurodegenerativas/enzimologia , Patentes como Assunto
4.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
5.
Life Sci ; 238: 116976, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634464

RESUMO

AIM: The purpose of the present study was to elucidate the protective effect of histone deacetylase 6 inhibitor ACY1215 on autophagy pathway in acute liver failure (ALF). MAIN METHODS: Lipopolysaccharide (LPS) and d-galactosamine (D-Gal) were used to induce ALF model in C57BL/6 mice. D-Gal and tumor necrosis factor alpha (TNF-α) were applied in L02 cell. Autophagy inhibitor 3-MA and ACY1215 were conducted to induce 3-MA group, ACY1215 group and ACY1215+3-MA group. RESULTS: ACY1215 improved liver histological and functional changes in ALF mice model, whereas the autophagy inhibitor 3-MA aggravated liver tissue pathological and functional damage in ALF mice model group. The apoptotic levels (including apoptotic index/rate and apoptotic proteins) in ALF mice and L02 cell were ameliorated with treatment ACY1215. 3-MA accentuated the apoptotic levels in ACY1215 group. D-Gal/TNF-α could reduce L02 cell mitochondrial membrane potential (ΔΨm) in control group. ACY1215 increased the ΔΨm in ALF model. 3-MA also further reduced the ΔΨm in ACY1215 group. ACY1215 could induce autophagy in ALF mice and cell model group accompanied with an increase in expression of LC3-II and beclin-1 proteins and down-regulation of p62 protein. Moreover, the expression of LC3-II and beclin1 proteins were greatly reduced and the expression of p62 protein was ascended after intervention with 3-MA in ACY1215 group. SIGNIFICANCE: Histone deacetylase 6 inhibitor ACY1215 could protect acute liver failure mice and L02 cell by inhibiting apoptosis pathway through enhancing autophagy way.


Assuntos
Autofagia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Falência Hepática Aguda/prevenção & controle , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose , Autofagia/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
6.
Neurochem Res ; 44(11): 2460-2469, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31571096

RESUMO

Chemotherapy-related cognitive impairment (CRCI) is a potential long-term side effect during cancer treatment. There are currently no effective treatments for CRCI. Reduction or inhibition of histone deacetylase 6 (HDAC6) has been considered a possible therapeutic strategy for cognitive deficits. HDAC6 inhibition recently has been shown to reverse chemotherapy-induced peripheral neuropathy effectively. In the present study, we examined the effect of HDAC6 inhibitor ACY-1215 (Ricolinostat) on cisplatin-induced brain damage and cognitive deficits in mice. Our results showed that ACY-1215 ameliorated behavioral deficits and dendritic spine loss and increased synaptic density in cisplatin-treated mice. Mechanistically, HDAC6 inhibitor ACY-1215 enhanced α-tubulin acetylation in the hippocampus of cisplatin-treated mice. Furthermore, ACY-1215 recovered cisplatin-induced impaired mitochondrial transport and mitochondrial dysfunction in the hippocampus. Our results suggest that inhibition of HDAC6 improves established cisplatin-induced cognitive deficits by the restoration of mitochondrial and synaptic impairments. These results offer prospective approaches for CRCI, especially because ACY1215 currently serves as an add-on cancer therapy during clinical trials.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ácidos Hidroxâmicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Cisplatino , Disfunção Cognitiva/induzido quimicamente , Espinhas Dendríticas/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacocinética , Pirimidinas/farmacocinética
7.
Eur J Med Chem ; 184: 111755, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31627059

RESUMO

Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed additional low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast cancer and four hematological cancer cell lines was supported by pharmacodynamic studies on a preferred molecule, 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modelling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compound potency, explaining the observed HDAC3/6 selectivity. A subset of the compounds also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favourable DMPK profile warranting further investigation of the therapeutic potential of these compounds.


Assuntos
Antimaláricos/farmacologia , Descoberta de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ratos , Relação Estrutura-Atividade
8.
Mol Med Rep ; 20(4): 3363-3370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432127

RESUMO

The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid ß protein alloform 1­40 (Aß1­40) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aß1­40 co­injection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by co­injection of APOE4 + Aß1­40. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcription­quantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubule­associated protein tau and glycogen synthase kinase 3ß (GSK3ß). APOE4 and Aß1­40 co­aggregation decreased the short­term spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aß1­40 co­aggregation­induced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aß1­40 co­aggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3ß protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3ß phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aß1­40 co­aggregation in model rats.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Lesões Encefálicas/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Desacetilase 6 de Histona/biossíntese , Inibidores de Histona Desacetilases/farmacologia , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Colina O-Acetiltransferase/biossíntese , Hipocampo/patologia , Hipocampo/fisiopatologia , Desacetilase 6 de Histona/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/fisiopatologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
9.
Int J Oncol ; 55(2): 499-512, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268156

RESUMO

Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose­limiting toxicities in patients with multiple myeloma (MM). The present study investigated the interaction between the HDAC6 inhibitor, A452, and immunomodulatory drugs (IMiDs) on dexamethasone (Dex)­sensitive and ­resistant MM cells compared with the current clinically tested HDAC6 inhibitor, ACY­1215. It was shown that the combination of the HDAC6­selective inhibitor, A452, with either of the IMiDs tested (lenalidomide or pomalidomide) led to the synergistic inhibition of cell growth, a decrease in the viability of MM cells and in an increase in the levels of apoptosis. Furthermore, enhanced cell death was associated with the inactivation of AKT and extracellular signal­regulated kinase (ERK)1/2. Of note, A452 in combination with IMiDs induced synergistic MM cytotoxicity without altering the expression of cereblon and thereby, the synergistic downregulation of IKAROS family zinc finger (IKZF)1/3, c­Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD­L1. More importantly, this combination treatment was effective in the Dex­resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY­1215. Taken together, these findings suggest that a combination of the HDAC6­selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.


Assuntos
Sinergismo Farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Fatores Imunológicos/farmacologia , Mieloma Múltiplo/patologia , Apoptose , Derivados de Benzeno/farmacologia , Proliferação de Células , Humanos , Lenalidomida/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Células Tumorais Cultivadas
10.
Biosci Trends ; 13(3): 267-272, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31155552

RESUMO

In the field of epigenetics, histone deacetylases (HDACs) are important members and well validated targets for anti-cancer drugs discovery. In this study, we designed and synthesized twenty-seven novel hydroxamic acid-based HDAC inhibitors (HDACis) with benzyl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward HDACs. Among them, compounds ZM-22 to ZM-27 with inhibition rates more than 90% toward HDACs exhibited potent inhibitory activity toward HDAC6, and ZM-23 possessed the best selectivity to HDAC6 over HDAC1. The high potency of compound ZM-23 toward HDAC6 was rationalized by molecular docking simulation. This series of compounds is worthy for further anti-cancer activity evaluation and structural optimization works.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Triazóis/química , Células HeLa , Inibidores de Histona Desacetilases/farmacologia , Humanos , Simulação de Acoplamento Molecular
11.
Pharm Biol ; 57(1): 263-268, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31124385

RESUMO

Context: Researchers in a variety of fields have extensively focused on histone deacetylase 6 (HDAC6) due to its aggravation of inflammatory reaction. However, relevant studies examining whether HDAC6 could exacerbate lipopolysaccharide (LPS)-induced inflammation are still lacking. Objective: We assessed the role of HDAC6 in LPS-induced brain inflammation and used the HDAC6-selective inhibitor Tubastatin A (TBSA) to investigate the potential mechanisms further. Materials and methods: Brain inflammation was induced in Kunming (KM) mice via intraperitoneal (I.P.), injection of Lipopolysaccharide (LPS) (1 mg/kg), the TBSA (0.5 mg/kg) was delivered via intraperitoneal. The phosphorylated p38 (p-p38) Mitogen-activated protein kinases (MAPK) and expression of typical inflammatory mediators, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in both the hippocampus and cortex, were examined by immunoblotting. Nissl staining was used to detect the neuronal damage in the hippocampus and the cortex. Results: About 1 mg/kg LPS via daily intraperitoneal (I.P.) injections for 12 days significantly increased p38 MAPK phosphorylation, TNF-α and IL-6 expression, and neuronal loss. However, 0.5 mg/kg TBSA (three days before LPS treatment) by I.P. injections for 15 days could reverse the above results. Conclusions: This present study provided evidence that TBSA significantly suppressed LPS-induced neuroinflammation and the expression of p-p38. Results derived from our study might help reveal the effective targeting strategies of LPS-induced brain inflammation through inhibiting HDAC6.


Assuntos
Encefalite/prevenção & controle , Inibidores Enzimáticos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Lipopolissacarídeos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Modelos Animais de Doenças , Encefalite/enzimologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos , Fosforilação
12.
Arch Pharm (Weinheim) ; 352(6): e1900026, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31056792

RESUMO

Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti-inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat-100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat-100. Here, we present the enantioselective synthesis of small-molecule compounds based on the tetrahydro-ß-carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S-derivative S-21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by Ki values in the range of 0.5-2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac-tubulin as surrogate parameter.


Assuntos
Carbolinas/química , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Acetilação , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Solubilidade , Estereoisomerismo
13.
J Enzyme Inhib Med Chem ; 34(1): 1062-1077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072216

RESUMO

Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio-N-hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a. Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias do Plexo Corióideo/tratamento farmacológico , Desenho de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Plexo Corióideo/metabolismo , Neoplasias do Plexo Corióideo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Estrutura Molecular , Relação Estrutura-Atividade
14.
Nat Cell Biol ; 21(5): 592-602, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962575

RESUMO

Inverted formin 2 (INF2) is a member of the formin family of actin assembly factors. Dominant missense mutations in INF2 are linked to two diseases: focal segmental glomerulosclerosis, a kidney disease, and Charcot-Marie-Tooth disease, a neuropathy. All of the disease mutations map to the autoinhibitory diaphanous inhibitory domain. Interestingly, purified INF2 is not autoinhibited, suggesting the existence of other cellular inhibitors. Here, we purified an INF2 inhibitor from mouse brain tissue, and identified it as a complex of lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP). Inhibition of INF2 by CAP-KAc-actin is dependent on the INF2 diaphanous inhibitory domain (DID). Treatment of CAP-KAc-actin-inhibited INF2 with histone deacetylase 6 releases INF2 inhibition, whereas inhibitors of histone deacetylase 6 block the activation of cellular INF2. Disease-associated INF2 mutants are poorly inhibited by CAP-KAc-actin, suggesting that focal segmental glomerulosclerosis and Charcot-Marie-Tooth disease result from reduced CAP-KAc-actin binding. These findings reveal a role for KAc-actin in the regulation of an actin assembly factor by a mechanism that we call facilitated autoinhibition.


Assuntos
Actinas/genética , Proteínas de Transporte/genética , Doença de Charcot-Marie-Tooth/genética , Glomerulosclerose Segmentar e Focal/genética , Proteínas dos Microfilamentos/genética , Actinas/química , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte/química , Doença de Charcot-Marie-Tooth/patologia , Glomerulosclerose Segmentar e Focal/patologia , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/genética , Humanos , Lisina/química , Camundongos , Proteínas dos Microfilamentos/química , Mutação , Ligação Proteica , Domínios Proteicos/genética
15.
Int J Mol Sci ; 20(7)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30935091

RESUMO

Recent studies show that histone deacetylase 6 (HDAC6) has important roles in the human brain, especially in the context of a number of nervous system disorders. Animal models of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders show that HDAC6 modulates important biological processes relevant to disease biology. Pan-selective histone deacetylase (HDAC) inhibitors had been studied in animal behavioral assays and shown to induce synaptogenesis in rodent neuronal cultures. While most studies of HDACs in the nervous system have focused on class I HDACs located in the nucleus (e.g., HDACs 1,2,3), recent findings in rodent models suggest that the cytoplasmic class IIb HDAC, HDAC6, plays an important role in regulating mood-related behaviors. Human studies suggest a significant role for synaptic dysfunction in the prefrontal cortex (PFC) and hippocampus in depression. Studies of HDAC inhibitors (HDACi) in human neuronal cells show that HDAC6 inhibitors (HDAC6i) increase the acetylation of specific lysine residues in proteins involved in synaptogenesis. This has led to the hypothesis that HDAC6i may modulate synaptic biology not through effects on the acetylation of histones, but by regulating acetylation of non-histone proteins.


Assuntos
Desacetilase 6 de Histona/metabolismo , Neurônios/citologia , Diferenciação Celular/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/metabolismo , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Humanos , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Biosci Trends ; 13(1): 91-97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867374

RESUMO

In epigenetics, histone deacetylases (HDACs) are well validated targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of twenty two novel (E)-N-hydroxycinnamamide-based HDAC inhibitors with 4-aminopiperidine1-carboxamide as the core structure. Most newly synthesized compounds displayed high inhibition rates toward HDAC at the concentration of 1 µM. Among them, the inhibition rates of compounds LYP-2, LYP-3, LYP-6, and LYP-15 were more than 75%. Furthermore, compounds LYP-2, LYP-3, and LYP-6 potently inhibited the activity of HDAC6 with selectivity over HDAC1. We chose LYP-2 and LYP-6 to test its antiproliferative effect on breast cancer cells MCF-7. Either LYP-2 or LYP-6 alone moderately suppressed the cell growth, but could synergistically enhance the inhibitory effect of bortezomib. These results suggested that combined HDAC6 inhibitor and bortezomib regimen might be an option for breast cancer treatment.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Ácidos Cumáricos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Piperidinas/farmacologia , Amidas/síntese química , Antineoplásicos/síntese química , Ácidos Cumáricos/síntese química , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/síntese química , Humanos , Células MCF-7 , Piperidinas/síntese química
17.
Mol Med ; 25(1): 10, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925865

RESUMO

BACKGROUND: The pathological features of aortic dissection (AD) include vascular smooth muscle cell (VSMC) loss, elastic fiber fraction, and inflammatory responses in the aorta. However, little is known about the post-translational modification mechanisms responsible for these biological processes. METHODS: A total of 72 aorta samples, used for protein detection, were collected from 36 coronary artery disease (CAD, served as the control) patients and 36 type A AD (TAAD) patients. Chromatin immunoprecipitation (ChIP)-PCR was used to identify the genes regulated by H3K23ac, and tubastatin A, an inhibitor of HDAC6, was utilized to clarify the downstream mechanisms regulated by HDAC6. RESULTS: We found that the protein level of histone deacetylase HDAC6 was reduced in the aortas of patients suffering from TAAD and that the protein levels of H4K12ac, and H3K23ac significantly increased, while H3K18ac, H4K8ac, and H4K5ac dramatically decreased when compared with CAD patients. Although H3K23ac, H3K18ac, and H4K8ac increased in the human VSMCs after treatment with the HDAC6 inhibitor tubastatin A, only H3K23ac showed the same results in human tissues. Notably, the results of ChIP-PCR demonstrated that H3K23ac was enriched in extracellular matrix (ECM)-related genes, including Col1A2, Col3A1, CTGF, POSTN, MMP2, TIMP2, and ACTA2, in the aortic samples of TAAD patients. In addition, our results showed that HDAC6 regulates H4K20me2 and p-MEK1/2 in the pathological process of TAAD. CONCLUSIONS: These results indicate that HDAC6 is involved in human TAAD formation by regulating H3K23ac, H4K20me2 and p-MEK1/2, thus, providing a strategy for the treatment of TAAD by targeting protein post-translational modifications (PTMs), chiefly histone PTMs.


Assuntos
Aneurisma Dissecante/metabolismo , Aorta/metabolismo , Aneurisma Aórtico/metabolismo , Desacetilase 6 de Histona/metabolismo , Idoso , Animais , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Feminino , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Processamento de Proteína Pós-Traducional , Coelhos
18.
Biochem Pharmacol ; 163: 458-471, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30885763

RESUMO

Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which has PROTAC (proteolysis-targeting chimeras)-like property resulted in both p62 accumulation and proteasomal degradation, leading to proteolysis of aberrantly overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 decreased cell migration, increased autophagic cancer cell death and significant tumor growth inhibition. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity. These results demonstrate that J22352 promotes HDAC6 degradation and induces anticancer effects by inhibiting autophagy and eliciting the antitumor immune response in glioblastoma. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and other cancers.


Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Neoplasias Experimentais/tratamento farmacológico , Quinazolinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Quinazolinas/química , Quinazolinas/farmacologia
19.
Biosci Rep ; 39(3)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30782785

RESUMO

Multiple myeloma (MM) is a hematological malignancy of plasma cells that produce a monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, challenges such as resistance to therapy remain. Currently, inhibition of histone deacetylases (HDACs) is emerging as a potential method for treating cancers. Numerous HDAC inhibitors are being studied for the use in monotherapy or in conjunction with other agents for MM. In the present study, we investigated the anti-myeloma effect of Nexturastat A (NexA), a novel selective HDAC6 inhibitor. We found that NexA impaired MM cells viability in a dose- and time-dependent manner. NexA also provoked a cell cycle arrest at the G1 phase in MM cells. Furthermore, NexA promoted apoptosis of MM cells via transcriptional activation of the p21 promoter, which may through its ability to up-regulate the H3Ac and H4Ac levels. Additionally, NexA could overcome bortezomib (BTZ) resistance in MM cells, and NexA in combination with BTZ had stronger efficacy. We also confirmed that NexA inhibited tumor growth in murine xenograft models of MM. These interesting findings provided the rationale for the future advancement of this novel HDAC6 inhibitor as a potential therapeutic anti-myeloma agent.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Carga Tumoral/efeitos dos fármacos
20.
Chem Biol Drug Des ; 93(5): 910-925, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30667160

RESUMO

Human histone deacetylase isoform 6 (HDAC6) has been shown to have an immense role in cell motility and aggresome formation and is being an attractive selective target for the treatment of multiple tumour types and neurodegenerative conditions. The discovery of selective HDAC6 inhibitors with new chemical functionalities is therefore of utmost interest to researchers. In order to examine the structural requirements for HDAC6-specific inhibitors and to derive predictive model which can be used for designing new selective HDAC6 inhibitors, a three-dimensional quantitative structure-activity relationship study was carried out on a diverse set of ligands using common feature-based pharmacophore alignment followed by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models displayed high correlation of 0.978 and 0.991 for best CoMFA and CoMSIA models, respectively, and a good statistical significance. The model could be used for predicting activities of the test set compounds as well as for deriving useful information regarding steric, electrostatic, hydrophobic properties of the molecules used in this study. Further, the training and test set molecules were docked into the HDAC6 binding site and molecular dynamics was carried out to suggest structural requirements for design of new inhibitors.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Sítios de Ligação , Desenho de Drogas , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Humanos , Análise dos Mínimos Quadrados , Ligantes , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade
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