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[PMID]:29482389
[Au] Autor:Elzahabi HSA; Nossier ES; Khalifa NM; Alasfoury RA; El-Manawaty MA
[Ad] Endereço:a Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt.
[Ti] Título:Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold.
[So] Source:J Enzyme Inhib Med Chem;33(1):546-557, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC : 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC : 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR ß, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Quinase 4 Dependente de Ciclina/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
Pirimidinas/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Quinase 4 Dependente de Ciclina/metabolismo
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Pirimidinas/síntese química
Pirimidinas/química
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrimidines); 0 (pyrido(3,2-d)pyrimidine); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437729


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[PMID]:29385210
[Au] Autor:Eadie LN; Dang P; Goyne JM; Hughes TP; White DL
[Ad] Endereço:Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.
[Ti] Título:ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells.
[So] Source:PLoS One;13(1):e0192180, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of nilotinib (to 2 µM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced nilotinib IC50 (p<0.001) indicating ABCC6 is likely involved in nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to nilotinib and dasatinib resistance in vitro. With nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy.
[Mh] Termos MeSH primário: Dasatinibe/farmacologia
Leucócitos Mononucleares/efeitos dos fármacos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia
Inibidores de Proteínas Quinases/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Dasatinibe/farmacocinética
Resistência a Medicamentos Antineoplásicos
Proteínas de Fusão bcr-abl/metabolismo
Seres Humanos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Inibidores de Proteínas Quinases/farmacocinética
Pirimidinas/farmacocinética
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide); 0 (ABCC6 protein, human); 0 (Multidrug Resistance-Associated Proteins); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (RNA, Messenger); EC 2.7.10.2 (Fusion Proteins, bcr-abl); RBZ1571X5H (Dasatinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0192180


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[PMID]:28457748
[Au] Autor:Schneider RK; Mullally A; Dugourd A; Peisker F; Hoogenboezem R; Van Strien PMH; Bindels EM; Heckl D; Büsche G; Fleck D; Müller-Newen G; Wongboonsin J; Ventura Ferreira M; Puelles VG; Saez-Rodriguez J; Ebert BL; Humphreys BD; Kramann R
[Ad] Endereço:Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: r.k.schneider@erasmusmc.nl.
[Ti] Título:Gli1 Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.
[So] Source:Cell Stem Cell;20(6):785-800.e8, 2017 Jun 01.
[Is] ISSN:1875-9777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1 mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1 cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1 cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
Miofibroblastos/metabolismo
Mielofibrose Primária/tratamento farmacológico
Piridinas/farmacologia
Pirimidinas/farmacologia
Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/genética
Seres Humanos
Células Mesenquimais Estromais/patologia
Camundongos
Camundongos Transgênicos
Miofibroblastos/patologia
Mielofibrose Primária/genética
Mielofibrose Primária/metabolismo
Mielofibrose Primária/patologia
Proteína GLI1 em Dedos de Zinco/genética
Proteína GLI1 em Dedos de Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GANT 61); 0 (Gli protein, mouse); 0 (Pyridines); 0 (Pyrimidines); 0 (Zinc Finger Protein GLI1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29441966
[Au] Autor:Zhao H; Meng W; Li Y; Liu W; Fu B; Yang Y; Zhang Q; Chen G
[Ti] Título:The protective effects of CHIR99021 against oxidative injury in LO2 cells.
[So] Source:Pharmazie;71(11):629-635, 2016 11 02.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 µmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3ßSer9 , Bcl-2, Bcl-xl, survivin and ß-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3ß activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3ß/ß-catenin signaling pathway.
[Mh] Termos MeSH primário: Citoproteção/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Piridinas/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Antioxidantes/metabolismo
Apoptose/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
Quinase 3 da Glicogênio Sintase/biossíntese
Quinase 3 da Glicogênio Sintase/genética
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Necrose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Chir 99021); 0 (Pyridines); 0 (Pyrimidines); BBX060AN9V (Hydrogen Peroxide); EC 2.7.11.26 (Glycogen Synthase Kinase 3)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6714


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[PMID]:29267497
[Au] Autor:Caires A; Fernandes GS; Leme AM; Castino B; Pessoa EA; Fernandes SM; Fonseca CD; Vattimo MF; Schor N; Borges FT
[Ad] Endereço:Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.
[Ti] Título:Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats.
[So] Source:Braz J Med Biol Res;51(2):e6373, 2017 Dec 11.
[Is] ISSN:1414-431X
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.
[Mh] Termos MeSH primário: Lesão Renal Aguda/induzido quimicamente
Lesão Renal Aguda/prevenção & controle
Ciclosporina/toxicidade
Antagonistas do Receptor de Endotelina A/farmacologia
Imunossupressores/toxicidade
Pirimidinas/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Lesão Renal Aguda/fisiopatologia
Animais
Creatinina/sangue
Antagonistas do Receptor de Endotelina A/uso terapêutico
Hemodinâmica
Immunoblotting
Imuno-Histoquímica
Rim/efeitos dos fármacos
Rim/fisiopatologia
Masculino
Estresse Oxidativo/fisiologia
Substâncias Protetoras/farmacologia
Substâncias Protetoras/uso terapêutico
Pirimidinas/uso terapêutico
Ratos Endogâmicos SHR
Ratos Wistar
Reprodutibilidade dos Testes
Sulfonamidas/uso terapêutico
Resultado do Tratamento
Ureia/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin A Receptor Antagonists); 0 (Immunosuppressive Agents); 0 (Protective Agents); 0 (Pyrimidines); 0 (Sulfonamides); 83HN0GTJ6D (Cyclosporine); 8W8T17847W (Urea); AYI8EX34EU (Creatinine); Q326023R30 (bosentan); Z9K9Y9WMVL (macitentan)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


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[PMID]:28460083
[Au] Autor:Rendas-Baum R; Kosinski M; Singh A; Mebus CA; Wilkinson BE; Wallenstein GV
[Ad] Endereço:QualityMetric Incorporated Lincoln, RI.
[Ti] Título:Estimated medical expenditure and risk of job loss among rheumatoid arthritis patients undergoing tofacitinib treatment: post hoc analyses of two randomized clinical trials.
[So] Source:Rheumatology (Oxford);56(8):1386-1394, 2017 Aug 01.
[Is] ISSN:1462-0332
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Objectives: RA causes high disability levels and reduces health-related quality of life, triggering increased costs and risk of unemployment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. These post hoc analyses of phase 3 data aimed to assess monthly medical expenditure (MME) and risk of job loss for tofacitinib treatment vs placebo. Methods: Data analysed were from two randomized phase 3 studies of RA patients (n = 1115) with inadequate response to MTX or TNF inhibitors (TNFi) receiving tofacitinib 5 or 10 mg twice daily, adalimumab (one study only) or placebo, in combination with MTX. Short Form 36 version 2 Health Survey physical and mental component summary scores were translated into predicted MME via an algorithm and concurrent inability to work and job loss risks at 6, 12 and 24 months, using Medical Outcomes Study data. Results: MME reduction by month 3 was $100 greater for tofacitinib- than placebo-treated TNFi inadequate responders (P < 0.001); >20 and 6% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾16%, and risk of future job loss decreased ∼20% (P < 0.001 vs placebo). MME reduction by month 3 was $70 greater for tofacitinib- than placebo-treated MTX inadequate responders (P < 0.001); ⩾23 and 13% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ⩾31% and risk of future job loss decreased ⩾25% (P < 0.001 vs placebo). Conclusion: Tofacitinib treatment had a positive impact on estimated medical expenditure and risk of job loss for RA patients with inadequate response to MTX or TNFi.
[Mh] Termos MeSH primário: Antirreumáticos/economia
Artrite Reumatoide/economia
Efeitos Psicossociais da Doença
Gastos em Saúde
Piperidinas/economia
Pirimidinas/economia
Pirróis/economia
Retorno ao Trabalho/estatística & dados numéricos
[Mh] Termos MeSH secundário: Adalimumab/administração & dosagem
Adalimumab/economia
Adulto
Antirreumáticos/administração & dosagem
Artrite Reumatoide/tratamento farmacológico
Método Duplo-Cego
Quimioterapia Combinada
Feminino
Seres Humanos
Masculino
Metotrexato/administração & dosagem
Metotrexato/economia
Meia-Idade
Piperidinas/administração & dosagem
Pirimidinas/administração & dosagem
Pirróis/administração & dosagem
Fatores de Risco
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antirheumatic Agents); 0 (Piperidines); 0 (Pyrimidines); 0 (Pyrroles); 87LA6FU830 (tofacitinib); FYS6T7F842 (Adalimumab); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/rheumatology/kex087


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[PMID]:28453705
[Au] Autor:Mato AR; Hill BT; Lamanna N; Barr PM; Ujjani CS; Brander DM; Howlett C; Skarbnik AP; Cheson BD; Zent CS; Pu JJ; Kiselev P; Foon K; Lenhart J; Henick Bachow S; Winter AM; Cruz AL; Claxton DF; Goy A; Daniel C; Isaac K; Kennard KH; Timlin C; Fanning M; Gashonia L; Yacur M; Svoboda J; Schuster SJ; Nabhan C
[Ad] Endereço:Center for CLL, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
[Ti] Título:Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.
[So] Source:Ann Oncol;28(5):1050-1056, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem
Intervalo Livre de Doença
Esquema de Medicação
Seres Humanos
Estimativa de Kaplan-Meier
Leucemia Linfocítica Crônica de Células B/mortalidade
Meia-Idade
Modelos de Riscos Proporcionais
Purinas/administração & dosagem
Pirazóis/administração & dosagem
Pirimidinas/administração & dosagem
Quinazolinonas/administração & dosagem
Estudos Retrospectivos
Sulfonamidas/administração & dosagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (PCI 32765); 0 (Purines); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Quinazolinones); 0 (Sulfonamides); N54AIC43PW (venetoclax); YG57I8T5M0 (idelalisib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx031


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[PMID]:29466156
[Au] Autor:Drilon A; Laetsch TW; Kummar S; DuBois SG; Lassen UN; Demetri GD; Nathenson M; Doebele RC; Farago AF; Pappo AS; Turpin B; Dowlati A; Brose MS; Mascarenhas L; Federman N; Berlin J; El-Deiry WS; Baik C; Deeken J; Boni V; Nagasubramanian R; Taylor M; Rudzinski ER; Meric-Bernstam F; Sohal DPS; Ma PC; Raez LE; Hechtman JF; Benayed R; Ladanyi M; Tuch BB; Ebata K; Cruickshank S; Ku NC; Cox MC; Hawkins DS; Hong DS; Hyman DM
[Ad] Endereço:From Memorial Sloan Kettering Cancer Center (A. Drilon, J.F.H., R.B., M.L., D.M.H.) and Weill Cornell Medical College (A. Drilon, D.M.H.), New York; University of Texas Southwestern Medical Center-Children's Health, Dallas (T.W.L.); Stanford Cancer Center, Stanford University, Palo Alto (S.K.), Chil
[Ti] Título:Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
[So] Source:N Engl J Med;378(8):731-739, 2018 02 22.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias/tratamento farmacológico
Pirazóis/uso terapêutico
Pirimidinas/uso terapêutico
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Criança
Pré-Escolar
Intervalo Livre de Doença
Feminino
Seres Humanos
Lactente
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Neoplasias/química
Proteínas de Fusão Oncogênicas/análise
Proteínas Quinases/análise
Proteínas Quinases/genética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ARRY-470); 0 (Antineoplastic Agents); 0 (Oncogene Proteins, Fusion); 0 (Pyrazoles); 0 (Pyrimidines); EC 2.7.- (Protein Kinases); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.11.28 (tropomyosin kinase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180222
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1714448


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[PMID]:29358147
[Au] Autor:Long L; Luo Y; Hou ZJ; Ma HJ; Long ZJ; Tu ZC; Huang LJ; Liu Q; Lu G
[Ad] Endereço:Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
[Ti] Título:Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold.
[So] Source:Eur J Med Chem;145:805-812, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The inhibition of the members of aurora kinase family using ATP-competitive small molecules is an effective method for anticancer therapeutics. Based on our previous work, we synthesized 12 new N-trisubstituted pyrimidine derivatives and evaluated their biological activities and stabilities. Among them, compound 11j showed the best inhibition against aurora A kinase (IC = 7.1 nM), human leukemia cell line U937 (IC = 12.2 nM) and the growth of U937 xenograft tumors in vivo. By the flow cytometry and immunofluorescence analysis of U937, we found that compound 11j can induced polyploidy formation including (4N, 8N and 16N) and induce defects in both chromosome alignment and spindle formation. Furthermore, compound 11j exhibited good chemical, physical, and thermal stabilities. All these results suggested that 11j is a promising lead compound for further development of anticancer drugs.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Aurora Quinase A/antagonistas & inibidores
Aurora Quinase A/metabolismo
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
Camundongos Nus
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/patologia
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Células U937
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); EC 2.7.11.1 (Aurora Kinase A)
[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:180124
[St] Status:MEDLINE


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[PMID]:29353724
[Au] Autor:Jin K; Yin H; De Clercq E; Pannecouque C; Meng G; Chen F
[Ad] Endereço:Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
[Ti] Título:Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1.
[So] Source:Eur J Med Chem;145:726-734, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC value of 1 nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild-type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the π-π stacking effect between the target molecule and the non-nucleoside inhibitor-binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Compostos de Bifenilo/farmacologia
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Pirimidinas/farmacologia
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Compostos de Bifenilo/química
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Descoberta de Drogas
Transcriptase Reversa do HIV/metabolismo
HIV-1/genética
Seres Humanos
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Estrutura Molecular
Mutação
Pirimidinas/síntese química
Pirimidinas/química
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Biphenyl Compounds); 0 (Pyrimidines); 0 (Reverse Transcriptase Inhibitors); 2L9GJK6MGN (diphenyl); EC 2.7.7.49 (HIV Reverse Transcriptase)
[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:180123
[St] Status:MEDLINE



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