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[PMID]: 29237530 [Au] Autor: Zhu XH; Li QG; Wang J; Hu GZ; Liu ZQ; Hu QH; Wu G [Ad] Endereço: School of Medicine, Nanchang University, Nanchang 330006, China. nclqg2017@163.com. [Ti] Título: [Mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice]. [So] Source: Zhongguo Dang Dai Er Ke Za Zhi;19(12):1278-1284, 2017 Dec. [Is] ISSN: 1008-8830 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 µg/g). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at 24 hours after the last challenge, and the total number of cells and percentage of eosinophils in BALF were calculated. Pathological staining was performed to observe histopathological changes in lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression of E-cadherin and vimentin during epithelial-mesenchymal transition (EMT). RESULTS: Compared with the control group, the OVA group had marked infiltration of inflammatory cells in the airway, thickening of the airway wall, increased secretion of mucus, and increases in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the OVA group, the JQ1+OVA group had significantly alleviated airway inflammatory response and significant reductions in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the control group, the OVA group had significant reductions in the mRNA and protein expression of E-cadherin and significant increases in the mRNA and protein expression of vimentin (P<0.01); compared with the OVA group, the JQ1+OVA group had significant increases in the mRNA and protein expression of E-cadherin and significant reductions in the mRNA and protein expression of vimentin (P<0.01); there were no significant differences in these indices between the JQ1+OVA group and the control group (P>0.05). CONCLUSIONS: Mice with OVA-induced asthma have airway remodeling during EMT. BET bromodomain inhibitor JQ1 can reduce airway inflammation, inhibit EMT, and alleviate airway remodeling, which provides a new direction for the treatment of asthma. [Mh] Termos MeSH primário: Remodelação das Vias Aéreas/efeitos dos fármacos Asma/tratamento farmacológico Azepinas/farmacologia Triazóis/farmacologia [Mh] Termos MeSH secundário: Animais Caderinas/análise Caderinas/genética Transição Epitelial-Mesenquimal Feminino Camundongos Proteínas Nucleares/antagonistas & inibidores Ovalbumina/imunologia RNA Mensageiro/análise Fatores de Transcrição/antagonistas & inibidores Vimentina/análise Vimentina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 ((+)-JQ1 compound); 0 (Azepines); 0 (Brd4 protein, mouse); 0 (Cadherins); 0 (E-cadherin protein, mouse); 0 (Nuclear Proteins); 0 (RNA, Messenger); 0 (Transcription Factors); 0 (Triazoles); 0 (Vimentin); 9006-59-1 (Ovalbumin) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171215 [St] Status: MEDLINE

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[PMID]: 29335204 [Au] Autor: Gu X; Jiang Y; Qu Y; Chen J; Feng D; Li C; Yin X [Ad] Endereço: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China. [Ti] Título: Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors. [So] Source: Eur J Med Chem;145:379-388, 2018 Feb 10. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities. [Mh] Termos MeSH primário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores Antineoplásicos/farmacologia Azepinas/farmacologia Compostos de Bifenilo/farmacologia Neoplasias/tratamento farmacológico [Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo Antineoplásicos/síntese química Antineoplásicos/química Azepinas/química Compostos de Bifenilo/síntese química Compostos de Bifenilo/química Linhagem Celular Tumoral Relação Dose-Resposta a Droga Resistência a Múltiplos Medicamentos/efeitos dos fármacos Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos Ensaios de Seleção de Medicamentos Antitumorais Seres Humanos Células K562 Estrutura Molecular Neoplasias/metabolismo Neoplasias/patologia Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Biphenyl Compounds); 0G32E321W1 (bifendate) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180302 [Lr] Data última revisão: 180302 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180117 [St] Status: MEDLINE

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[PMID]: 29287727 [Au] Autor: Zhang HP; Li GQ; Zhang Y; Guo WZ; Zhang JK; Li J; Lv JF; Zhang SJ [Ad] Endereço: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, China; Henan Key Laborato [Ti] Título: Upregulation of Mcl-1 inhibits JQ1-triggered anticancer activity in hepatocellular carcinoma cells. [So] Source: Biochem Biophys Res Commun;495(4):2456-2461, 2018 01 22. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Bromodomains and extra-terminal (BET) proteins inhibitors are promising cancer therapeutic agents. However, tumor cells often develop resistance to BET inhibitors, greatly limiting their therapeutic potential. To study the mechanism underlying the resistance of BET inhibitors in hepatocellular carcinoma (HCC) cells, we herein investigated the impact of BET inhibitor JQ1 on the gene expression of Bcl-2 family members by RNA sequencing analysis, and found that acute treatment with JQ1 triggered upregulation of Mcl-1 in HCCLM3 and BEL7402 cell lines. This JQ1-triggered Mcl-1 upregulation was further confirmed by quantitative reverse transcription polymerase chain reaction and western blotting analysis, both at mRNA and protein levels. Inhibition of Mcl-1 by RNA interference dramatically enhanced JQ1-triggered caspase-3 activation, cleavage of poly (ADP-ribose) polymerase and apoptotic cell death induction in multiple HCC cell lines. Moreover, JQ1 in combination with cyclin-dependent kinase inhibitor flavopiridol at a subtoxic concentration that reduced expression of Mcl-1, triggered massive apoptotic cell death in HCCLM3 and BEL7402 cell lines. Together, these data suggest that Mcl-1 is a major contributor to BET inhibitor-resistance in HCC cells, and that combining drugs capable of down-regulating Mcl-1 may promote therapeutic potential in human HCC. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Azepinas/administração & dosagem Carcinoma Hepatocelular/tratamento farmacológico Carcinoma Hepatocelular/patologia Neoplasias Hepáticas/tratamento farmacológico Neoplasias Hepáticas/patologia Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo Triazóis/administração & dosagem [Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico Linhagem Celular Tumoral Células Hep G2 Seres Humanos Proteínas/antagonistas & inibidores Regulação para Cima/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 ((+)-JQ1 compound); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Proteins); 0 (Triazoles); 0 (bromodomain and extra-terminal domain protein, human) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171231 [St] Status: MEDLINE

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[PMID]: 29260599 [Au] Autor: Liewer S; Huddleston A [Ad] Endereço: a Department of Pharmacy , Nebraska Medicine , Omaha , NE , USA. [Ti] Título: Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. [So] Source: Expert Opin Investig Drugs;27(1):105-112, 2018 Jan. [Is] ISSN: 1744-7658 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types. [Mh] Termos MeSH primário: Azepinas/administração & dosagem Linfoma não Hodgkin/tratamento farmacológico Neoplasias/tratamento farmacológico Pirimidinas/administração & dosagem [Mh] Termos MeSH secundário: Animais Antineoplásicos/administração & dosagem Antineoplásicos/efeitos adversos Antineoplásicos/farmacocinética Apoptose/efeitos dos fármacos Aurora Quinase A/antagonistas & inibidores Azepinas/efeitos adversos Azepinas/farmacocinética Seres Humanos Linfoma não Hodgkin/patologia Neoplasias/patologia Inibidores de Proteínas Quinases/administração & dosagem Inibidores de Proteínas Quinases/efeitos adversos Inibidores de Proteínas Quinases/farmacocinética Pirimidinas/efeitos adversos Pirimidinas/farmacocinética Ensaios Clínicos Controlados Aleatórios como Assunto [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Azepines); 0 (MLN 8237); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); EC 2.7.11.1 (Aurora Kinase A) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171221 [St] Status: MEDLINE [do] DOI: 10.1080/13543784.2018.1417382

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[PMID]: 29298347 [Au] Autor: Grundy M; Seedhouse C; Jones T; Elmi L; Hall M; Graham A; Russell N; Pallis M [Ad] Endereço: Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom. [Ti] Título: Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling. [So] Source: PLoS One;13(1):e0190682, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents-notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors-sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Leucemia/patologia [Mh] Termos MeSH secundário: Azepinas/farmacologia Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia Linhagem Celular Tumoral Combinação de Medicamentos Seres Humanos Indóis/farmacologia Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores Sulfonamidas/farmacologia Triazóis/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 ((+)-JQ1 compound); 0 (A-1210477); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Drug Combinations); 0 (Indoles); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Sulfonamides); 0 (Triazoles); N54AIC43PW (venetoclax) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180104 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190682

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[PMID]: 29173760 [Au] Autor: Foy V; Schenk MW; Baker K; Gomes F; Lallo A; Frese KK; Forster M; Dive C; Blackhall F [Ad] Endereço: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK. [Ti] Título: Targeting DNA damage in SCLC. [So] Source: Lung Cancer;114:12-22, 2017 Dec. [Is] ISSN: 1872-8332 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease. [Mh] Termos MeSH primário: Dano ao DNA/genética Neoplasias Pulmonares/tratamento farmacológico Rad51 Recombinase/antagonistas & inibidores Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico [Mh] Termos MeSH secundário: Aurora Quinases/uso terapêutico Azepinas/uso terapêutico Benzimidazóis/uso terapêutico Carbolinas/uso terapêutico Pontos de Checagem do Ciclo Celular/efeitos dos fármacos Pontos de Checagem do Ciclo Celular/genética Proliferação Celular/efeitos dos fármacos Proliferação Celular/genética Citotoxinas/uso terapêutico Dano ao DNA/efeitos dos fármacos Reparo do DNA Etoposídeo/uso terapêutico Instabilidade Genômica/efeitos dos fármacos Instabilidade Genômica/genética Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico Seres Humanos Neoplasias Pulmonares/genética Terapia de Alvo Molecular/métodos Ftalazinas/uso terapêutico Piperazinas/uso terapêutico Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico Inibidores de Proteínas Quinases/uso terapêutico Pirimidinas/uso terapêutico Rad51 Recombinase/uso terapêutico Carcinoma de Pequenas Células do Pulmão/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Azepines); 0 (Benzimidazoles); 0 (Carbolines); 0 (Cytotoxins); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (MLN 8237); 0 (PM 01183); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 01O4K0631N (veliparib); 6PLQ3CP4P3 (Etoposide); 9QHX048FRV (talazoparib); EC 2.7.11.1 (Aurora Kinases); EC 2.7.7.- (Rad51 Recombinase); WOH1JD9AR8 (olaparib) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180131 [Lr] Data última revisão: 180131 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE

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[PMID]: 29202408 [Au] Autor: Medvedeva NI; Kazakova OB; Lopatina TV; Smirnova IE; Giniyatullina GV; Baikova IP; Kataev VE [Ad] Endereço: Ufa Institute of Chemistry of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054, Ufa, Russian Federation. [Ti] Título: Synthesis and antimycobacterial activity of triterpeni≿ A-ring azepanes. [So] Source: Eur J Med Chem;143:464-472, 2018 Jan 01. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 µM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 µM against MTB H37Rv and MICs 4, 1 and 1 µM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids. [Mh] Termos MeSH primário: Antituberculosos/farmacologia Azepinas/farmacologia Mycobacterium tuberculosis/efeitos dos fármacos Triterpenos/farmacologia [Mh] Termos MeSH secundário: Antituberculosos/síntese química Antituberculosos/química Azepinas/síntese química Azepinas/química Relação Dose-Resposta a Droga Testes de Sensibilidade Microbiana Estrutura Molecular Relação Estrutura-Atividade Triterpenos/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antitubercular Agents); 0 (Azepines); 0 (Triterpenes) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180101 [Lr] Data última revisão: 180101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE

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[PMID]: 27774624 [Au] Autor: Huang M; Zeng S; Zou Y; Shi M; Qiu Q; Xiao Y; Chen G; Yang X; Liang L; Xu H [Ad] Endereço: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [Ti] Título: The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation. [So] Source: Br J Pharmacol;174(1):101-115, 2017 01. [Is] ISSN: 1476-5381 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND AND PURPOSE: There is increasing evidence indicating that bromodomain and extra-terminal domain (BET) proteins play a critical role in the regulation of immune and inflammatory responses; however, their contribution to vascular inflammation has not yet been elucidated. In this study, we investigated the effect of inhibiting BET bromodomain on vascular inflammation and the underlying mechanisms. EXPERIMENTAL APPROACH: HUVECs were isolated from fresh umbilical cords. JQ1, a specific BET bromodomain inhibitor, and Brd shRNA were used to evaluate the regulation of the BET proteins in vascular inflammation. Leukocyte adhesion to HUVECs was measure by an adhesion assay. Western blot or immunohistochemical analysis was used to detect the protein expression. Real-time PCR was used to evaluate mRNA expression. Leukocyte accumulation in vivo was determined by an acute lung inflammation model. KEY RESULTS: BET bromodomain inhibition suppressed the expression of adhesion molecules induced by TNF-α- or LPS, including ICAM-1, VCAM-1 and E-selectin, and inhibited leukocyte adhesion to activated HUVEC monolayers. Treatment with JQ1 also attenuated the LPS-induced accumulation of leukocytes and expression of endothelial adhesion molecules in the acute lung inflammation model in vivo. Furthermore, BET bromodomain inhibition reduced the activity of p38 and JNK MAPKs and NF-κB in TNF-α-stimulated HUVECs. TNF-α-induced NF-κB activation was also blocked by inhibitors of p38 (SB203580) or JNK (SP600125). CONCLUSIONS AND IMPLICATIONS: BET bromodomain is important for regulating endothelial inflammation. Strategies targeting endothelial BET bromodomain may provide a new therapeutic approach for controlling inflammatory-related diseases. [Mh] Termos MeSH primário: Azepinas/farmacologia Inflamação/tratamento farmacológico Proteínas Quinases Ativadas por Mitógeno/metabolismo NF-kappa B/metabolismo Inibidores de Proteínas Quinases/farmacologia Fatores de Transcrição/antagonistas & inibidores Fatores de Transcrição/metabolismo Triazóis/farmacologia [Mh] Termos MeSH secundário: Células Cultivadas Relação Dose-Resposta a Droga Ativação Enzimática/efeitos dos fármacos Seres Humanos Inflamação/metabolismo Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 ((+)-JQ1 compound); 0 (Azepines); 0 (NF-kappa B); 0 (Protein Kinase Inhibitors); 0 (Transcription Factors); 0 (Triazoles); EC 2.7.11.24 (Mitogen-Activated Protein Kinases) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180101 [Lr] Data última revisão: 180101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.1111/bph.13657

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[PMID]: 28938137 [Au] Autor: Huang D; Huang L; Zhang Q; Li J [Ad] Endereço: Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China. [Ti] Título: Synthesis and biological evaluation of novel 6,11-dihydro-5H-benzo[e]pyrimido- [5,4-b][1,4]diazepine derivatives as potential c-Met inhibitors. [So] Source: Eur J Med Chem;140:212-228, 2017 Nov 10. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Over expression of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein a series of novel 6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepine derivatives were designed, synthesised and evaluated for their c-Met kinase inhibition. Compounds 17e, 17f, 18a, and 18b were further examined for their anti-proliferative activities against four typical cancer cell lines (PC-3, Panc-1, HepG2, and Caki-1). The promising compound 17f was identified as a multi-target receptor tyrosine kinase inhibitor, which also displayed favourable pharmacokinetic properties in rats, had an acceptable safety profile in preclinical studies, and significant anti-tumour activity in the Caki-1 tumour xenograft model. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Azepinas/farmacologia Inibidores de Proteínas Quinases/farmacologia Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores [Mh] Termos MeSH secundário: Animais Antineoplásicos/síntese química Antineoplásicos/química Azepinas/síntese química Azepinas/química Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Ensaios de Seleção de Medicamentos Antitumorais Feminino Seres Humanos Masculino Camundongos Camundongos Endogâmicos Camundongos Nus Estrutura Molecular Inibidores de Proteínas Quinases/síntese química Inibidores de Proteínas Quinases/química Proteínas Proto-Oncogênicas c-met/metabolismo Ratos Ratos Sprague-Dawley Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Azepines); 0 (Protein Kinase Inhibitors); EC 2.7.10.1 (Proto-Oncogene Proteins c-met) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170923 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 28854735 [Au] Autor: Wang S; Pike AM; Lee SS; Strong MA; Connelly CJ; Greider CW [Ad] Endereço: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. [Ti] Título: BRD4 inhibitors block telomere elongation. [So] Source: Nucleic Acids Res;45(14):8403-8410, 2017 Aug 21. [Is] ISSN: 1362-4962 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated. [Mh] Termos MeSH primário: Proteínas Nucleares/genética Homeostase do Telômero/genética Encurtamento do Telômero/genética Fatores de Transcrição/genética [Mh] Termos MeSH secundário: Acetanilidas/farmacologia Animais Azepinas/farmacologia Southern Blotting Linhagem Celular Relação Dose-Resposta a Droga Fibroblastos/citologia Fibroblastos/efeitos dos fármacos Fibroblastos/metabolismo Expressão Gênica/efeitos dos fármacos Células HeLa Compostos Heterocíclicos com 3 Anéis/farmacologia Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia Seres Humanos Hibridização in Situ Fluorescente Camundongos Morfolinas/farmacologia Proteínas Nucleares/antagonistas & inibidores Proteínas Nucleares/metabolismo Pironas/farmacologia Interferência de RNA Telomerase/genética Telomerase/metabolismo Telômero/efeitos dos fármacos Telômero/enzimologia Telômero/genética Homeostase do Telômero/efeitos dos fármacos Encurtamento do Telômero/efeitos dos fármacos Fatores de Transcrição/antagonistas & inibidores Fatores de Transcrição/metabolismo Triazóis/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 ((+)-JQ1 compound); 0 (2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one); 0 (Acetanilides); 0 (Azepines); 0 (BRD4 protein, human); 0 (Brd4 protein, mouse); 0 (GSK1210151A); 0 (Heterocyclic Compounds, 3-Ring); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Morpholines); 0 (Nuclear Proteins); 0 (OTX015); 0 (Pyrones); 0 (Transcription Factors); 0 (Triazoles); EC 2.7.7.49 (Telomerase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170901 [St] Status: MEDLINE [do] DOI: 10.1093/nar/gkx561

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