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1.
Bioorg Med Chem Lett ; 30(2): 126787, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759849

RESUMO

The 11ß-hydroxysteroiddehydrogenase type 1(11ß-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11ß-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11ß-HSD1 and showed good 11ß-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11ß-HSD1 were suggested.

2.
World J Gastroenterol ; 25(39): 5936-5952, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660031

RESUMO

BACKGROUND: The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM: To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS: The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS: The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION: We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

3.
J Transl Med ; 17(1): 195, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182117

RESUMO

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

5.
J Med Chem ; 62(2): 575-588, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30623649

RESUMO

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.


Assuntos
Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Administração Oral , Animais , Antraquinonas/química , Antraquinonas/metabolismo , Antraquinonas/uso terapêutico , Sítios de Ligação , Linhagem Celular , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Masculino , Doenças Metabólicas/patologia , Doenças Metabólicas/veterinária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/patologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Ratos , Relação Estrutura-Atividade
6.
Biochem Biophys Res Commun ; 508(2): 451-457, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30503501

RESUMO

Sirtuins (SIRT1-7), a class of deacetylases, play major roles in DNA damage repair, aging, and metabolism in yeast and in mammals. SIRT7 is localized in the nucleolus. It regulates cellular processes, including genomic stability, rDNA transcription, and cell proliferation, and plays a role in tumorigenesis. SIRT7 deacetylates its substrates histone H3 (at lysine 18) and p53. p53, a tumor suppressor, induces apoptosis or cell cycle arrest and is stabilized by acetylation. p53 deacetylation at K382 by SIRT7 suppressed cancer cell growth by attenuating p53 activity. Therefore, identification of novel SIRT7 enzyme inhibitors is important. In this study, we found a novel inhibitor of SIRT7 (ID: 97491) that decreased SIRT7 activity in a dose-dependent manner. ID: 97491 induced expression of p53 and its acetylation by inhibited SIRT7. Moreover, ID: 97491 upregulated apoptotic effects through the caspase related proteins and inhibited cancer growth in vivo. The study results suggest that ID: 97491 can be a potential candidate to inhibit the deacetylase activity of SIRT7 and prevent tumor progression by increasing p53 stability through acetylation at K373/382.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Sirtuínas/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Progressão da Doença , Descoberta de Drogas , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Sirtuínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 18(1): 716, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976159

RESUMO

BACKGROUND: Although MASTL (microtubule-associated serine/threonine kinase-like) is a key mitotic kinase that regulates mitotic progression through the inactivation of tumor suppressor protein phosphatase 2A (PP2A), the antitumor mechanism of MASTL targeting in cancer cells is still unclear. METHODS: MASTL expression was evaluated by using breast cancer tissue microarrays and public cancer databases. The effects of MASTL depletion with siRNAs were evaluated in various breast cancer cells or normal cells. Various methods, including cell viability, cell cycle, soft agar, immunoblotting, immunofluorescence, PP2A activity, live image, and sphere forming assay, were used in this study. RESULTS: This study showed the oncosuppressive mechanism of MASTL targeting that promotes mitotic catastrophe through PP2A activation selectively in breast cancer cells. MASTL expression was closely associated with tumor progression and poor prognosis in breast cancer. The depletion of MASTL reduced the oncogenic properties of breast cancer cells with high MASTL expression, but did not affect the viability of non-transformed normal cells with low MASTL expression. With regard to the underlying mechanism, we found that MASTL inhibition caused mitotic catastrophe through PP2A activation in breast cancer cells. Furthermore, MASTL depletion enhanced the radiosensitivity of breast cancer cells with increased PP2A activity. Notably, MASTL depletion dramatically reduced the formation of radioresistant breast cancer stem cells in response to irradiation. CONCLUSION: Our data suggested that MASTL inhibition promoted mitotic catastrophe through PP2A activation, which led to the inhibition of cancer cell growth and a reversal of radioresistance in breast cancer cells.


Assuntos
Neoplasias da Mama/radioterapia , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Mitose , Proteína Fosfatase 2/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tolerância a Radiação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos da radiação , Prognóstico , Proteínas Proto-Oncogênicas/antagonistas & inibidores
8.
Biochem Biophys Res Commun ; 503(2): 882-887, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29928885

RESUMO

Bromodomain-containing protein 4 (Brd4) is known to play a key role in tumorigenesis. It binds acetylated histones to regulate the expression of numerous genes. Because of the importance of brd4 in tumorigenesis, much research has been undertaken to develop brd4 inhibitors with therapeutic potential. As a result, various scaffolds for bromodomain inhibitors have been identified. To discover new scaffolds, we performed mid-throughput screening using two different enzyme assays, alpha-screen and ELISA. We found a novel bromodomain inhibitor with a unique scaffold, aristoyagonine. This natural compound showed inhibitory activity in vitro and tumor growth inhibition in a Ty82-xenograft mouse model. In addition, we tested Brd4 inhibitors in gastric cancer cell lines, and found that aristoyagonine exerted cytotoxicity not only in I-BET-762-sensitive cancer cells, but also in I-BET-762-resistant cancer cells. This is the first paper to describe a natural compound as a Brd4 bromodomain inhibitor.


Assuntos
Produtos Biológicos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Isoquinolinas/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Neoplasias/prevenção & controle , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Arch Pharm Res ; 41(1): 46-56, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29103140

RESUMO

Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.


Assuntos
Antineoplásicos/farmacologia , Indazóis/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Bioorg Med Chem Lett ; 27(23): 5213-5220, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29103971

RESUMO

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.


Assuntos
Receptores Acoplados a Proteínas-G/agonistas , Tiazóis/farmacologia , Animais , Linhagem Celular , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
11.
Biochem Biophys Res Commun ; 492(1): 128-134, 2017 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-28782520

RESUMO

Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor and transcription regulator. Menin interacts with various proteins as a scaffold protein and is proposed to play important roles in multiple physiological and pathological processes by controlling gene expression, proliferation, and apoptosis. The mechanisms underlying menin's suppression of tumorigenesis are largely elusive. In this study, we showed that menin was essential for the regulation of canonical Wnt/ß-catenin signaling in cultured cells. The C-terminal domain of menin was able to directly interact with and promote ubiquitin-mediated degradation of ß-catenin. We further revealed that overexpression of menin down-regulated the transcriptional activity of ß-catenin and target gene expression. Moreover, menin efficiently inhibited ß-catenin protein levels, transcriptional activity, and proliferation of human renal carcinoma cells with an activated ß-catenin pathway. Taken together, our results provide novel molecular insights into the tumor suppressor activity of menin, which is partly mediated by proteasomal degradation of ß-catenin and inhibition of Wnt/ß-catenin signaling.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas/metabolismo , Ubiquitina/metabolismo , beta Catenina/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Ligação Proteica
12.
Biochem Pharmacol ; 144: 78-89, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813646

RESUMO

Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC.


Assuntos
Anti-Helmínticos/farmacologia , Autoantígenos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Niclosamida/farmacologia , Proteína Fosfatase 2/metabolismo , Anti-Helmínticos/uso terapêutico , Antinematódeos/farmacologia , Antinematódeos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Niclosamida/uso terapêutico
13.
Bioorg Med Chem Lett ; 27(16): 3909-3914, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28666737

RESUMO

A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.


Assuntos
Amidas/farmacologia , Desenho de Drogas , Receptores Acoplados a Proteínas-G/agonistas , Amidas/síntese química , Amidas/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
14.
Exp Mol Med ; 48: e252, 2016 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-27515126

RESUMO

Replication-independent incorporation of variant histone H3.3 has a profound impact on chromatin function and numerous cellular processes, including the differentiation of muscle cells. The histone chaperone HIRA and H3.3 have essential roles in MyoD regulation during myoblast differentiation. However, the precise mechanism that determines the onset of H3.3 deposition in response to differentiation signals is unclear. Here we show that HIRA is phosphorylated by Akt kinase, an important signaling modulator in muscle cells. By generating a phosphospecific antibody, we found that a significant amount of HIRA was phosphorylated in myoblasts. The phosphorylation level of HIRA and the occupancy of phosphorylated protein on muscle genes gradually decreased during cellular differentiation. Remarkably, the forced expression of the phosphomimic form of HIRA resulted in reduced H3.3 deposition and suppressed the activation of muscle genes in myotubes. Our data show that HIRA phosphorylation limits the expression of myogenic genes, while the dephosphorylation of HIRA is required for proficient H3.3 deposition and gene activation, demonstrating that the phosphorylation switch is exploited to modulate HIRA/H3.3-mediated muscle gene regulation during myogenesis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Chaperonas de Histonas/metabolismo , Desenvolvimento Muscular , Mioblastos/citologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Humanos , Camundongos , Mioblastos/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ativação Transcricional
15.
BMB Rep ; 48(12): 685-90, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26058396

RESUMO

The eukaryotic genome is packed into chromatin, which is important for the genomic integrity and gene regulation. Chromatin structures are maintained through assembly and disassembly of nucleosomes catalyzed by histone chaperones. Asf1 (anti-silencing function 1) is a highly conserved histone chaperone that mediates histone transfer on/off DNA and promotes histone H3 lysine 56 acetylation at globular core domain of histone H3. To elucidate the role of Asf1 in the modulation of chromatin structure, we screened and identified small molecules that inhibit Asf1 and H3K56 acetylation without affecting other histone modification. These pyrimidine-2,4,6-trione derivative molecules inhibited the nucleosome assembly mediated by Asf1 in vitro, and reduced the H3K56 acetylation in HeLa cells. Furthermore, production of HSV viral particles was reduced by these compounds. As Asf1 is implicated in genome integrity, cell proliferation, and cancer, current Asf1 inhibitor molecules may offer an opportunity for the therapeutic development for treatment of diseases.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Cromatina/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilação , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Histonas/metabolismo , Humanos , Chaperonas Moleculares , Nucleossomos/efeitos dos fármacos , Nucleossomos/metabolismo
16.
J Med Chem ; 58(7): 3002-24, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25734936

RESUMO

The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic α-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a new mechanistic class of "direct" c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 µM. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaio de Desvio de Mobilidade Eletroforética , Sequências Hélice-Alça-Hélice , Humanos , Concentração Inibidora 50 , Mimetismo Molecular , Ressonância Magnética Nuclear Biomolecular , Multimerização Proteica , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ressonância de Plasmônio de Superfície
17.
Biochem J ; 467(3): 425-38, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25695333

RESUMO

Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. In the present study, we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes (IEGs) of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signalling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signalling functions and their potential utility for elucidating ERK1/2 and other signalling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity.


Assuntos
Genes Precoces/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Simulação por Computador , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Células Jurkat , Ligantes , Sistema de Sinalização das MAP Quinases/genética , Melanoma/genética , Melanoma/patologia , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Fosforilação , Regiões Promotoras Genéticas/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-fos/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Elemento de Resposta Sérica , Fator de Transcrição AP-1/genética
18.
Bioorg Med Chem Lett ; 24(17): 4281-5, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25082125

RESUMO

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.


Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 70: 811-30, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24246730

RESUMO

Pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X3 receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (-NN-) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 ∼ 700 nM) at the hP2X3 receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13 h-n, dramatically improved the selectivity profiles of hP2X3 when compared with mP2X1 and hP2X7 receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X3 receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X3 receptor antagonist with an IC50 of 60 nM at hP2X3 and marginal antagonistic activities of 10 µM at mP2X1 and hP2X7. Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 µM 36j displaying 65% inhibition while 20 µM pregabalin, a clinically available drug, showed only 31% inhibition.


Assuntos
Desenho de Drogas , Dor/tratamento farmacológico , Dor/metabolismo , Fosfato de Piridoxal/análogos & derivados , Receptores Purinérgicos P2X3/metabolismo , Animais , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Fosfato de Piridoxal/síntese química , Fosfato de Piridoxal/química , Fosfato de Piridoxal/farmacologia , Relação Estrutura-Atividade , Xenopus
20.
Org Lett ; 15(13): 3234-7, 2013 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-23763721

RESUMO

In order to mimic amphipathic α-helices, a novel scaffold based on a 1,2-diphenylacetylene was designed. NMR and computational modeling confirmed that an intramolecular hydrogen bond favors conformations of the 1,2-diphenylacetylene that allow for accurate mimicry of the i, i + 7 and i + 2, i + 5 side chains found on opposing faces of an α-helix.


Assuntos
Acetileno/análogos & derivados , Peptídeos/química , Acetileno/química , Biomimética , Computadores Moleculares , Ligações de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Secundária de Proteína
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