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2.
Pharmacol Res ; 177: 106076, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35074524

RESUMO

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.


Assuntos
Produtos Biológicos , Farmacologia Clínica , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Agentes de Imunomodulação
3.
Int J Mol Sci ; 22(23)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34884436

RESUMO

Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary ß2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.


Assuntos
Nefropatias/urina , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Microglobulina beta-2/urina , Albuminas/metabolismo , Animais , Biomarcadores/urina , Modelos Animais de Doenças , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Microdissecção e Captura a Laser , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Biochem Biophys Res Commun ; 491(3): 681-686, 2017 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-28756225

RESUMO

Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD+), and NAD+ depletion ultimately results in cell death. The rate limiting step within the NAD+ salvage pathway required for converting nicotinamide to NAD+ is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD+ depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD+ synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD+ de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors. The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic.


Assuntos
Cianetos/administração & dosagem , Citocinas/antagonistas & inibidores , Citocinas/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/metabolismo , Guanidinas/administração & dosagem , NAD/biossíntese , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Anilidas , Apoptose/efeitos dos fármacos , Apoptose/genética , Arginina/análogos & derivados , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fibrossarcoma/genética , Humanos , Mutação/genética , NAD/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento
5.
PLoS One ; 10(3): e0114363, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25781882

RESUMO

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Leucemia Mieloide Aguda/patologia , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Janus Quinase 2/genética , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia
6.
J Pharmacol Exp Ther ; 343(3): 617-27, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22935731

RESUMO

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Compostos de Fenilureia/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Histonas/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Estrutura Molecular , Células NIH 3T3 , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/uso terapêutico , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Bioorg Med Chem Lett ; 22(14): 4750-5, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22695126

RESUMO

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Bioorg Med Chem Lett ; 22(9): 3208-12, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22465635

RESUMO

In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ureia/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Fator A de Crescimento do Endotélio Vascular
10.
J Biol Chem ; 286(51): 43951-43958, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-22020937

RESUMO

Eukaryotic elongation factor-2 kinase (eEF2K) relays growth and stress signals to protein synthesis through phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2). 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) is a widely accepted inhibitor of mammalian eEF2K and an efficacious anti-proliferation agent against different cancer cells. It implied that eEF2K could be an efficacious anticancer target. However, eEF2K siRNA was ineffective against cancer cells including those sensitive to NH125. To test if pharmacological intervention differs from siRNA interference, we identified a highly selective small molecule eEF2K inhibitor A-484954. Like siRNA, A-484954 had little effect on cancer cell growth. We carefully examined the effect of NH125 and A-484954 on phosphorylation of eEF2, the known cellular substrate of eEF2K. Surprisingly, NH125 increased eEF2 phosphorylation, whereas A-484954 inhibited the phosphorylation as expected for an eEF2K inhibitor. Both A-484954 and eEF2K siRNA inhibited eEF2K and reduced eEF2 phosphorylation with little effect on cancer cell growth. These data demonstrated clearly that the anticancer activity of NH125 was more correlated with induction of eEF2 phosphorylation than inhibition of eEF2K. Actually, induction of eEF2 phosphorylation was reported to correlate with inhibition of cancer cell growth. We compared several known inducers of eEF2 phosphorylation including AMPK activators and an mTOR inhibitor. Interestingly, stronger induction of eEF2 phosphorylation correlated with more effective growth inhibition. We also explored signal transduction pathways leading to NH125-induced eEF2 phosphorylation. Preliminary data suggested that NH125-induced eEF2 phosphorylation was likely mediated through multiple pathways. These observations identified an opportunity for a new multipathway approach to anticancer therapies.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imidazóis/farmacologia , Fator 2 de Elongação de Peptídeos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosforilação , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , eIF-2 Quinase/metabolismo
12.
Mol Cancer Ther ; 10(6): 949-59, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21471285

RESUMO

The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (AML; 15%-35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with AML harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo. We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3ß (GSK3ß). In addition, we show that inhibition of GSK3ß decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations.


Assuntos
Apoptose/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Humanos , Interleucina-3/metabolismo , Cloreto de Lítio/farmacologia , Mutação , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
13.
Toxicol Sci ; 121(1): 63-72, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21362633

RESUMO

Microcystis aeruginosa (M. aeruginosa) is a cosmopolitan Gram-negative cyanobacterium that may contaminate freshwater by releasing toxins, such as lipopolysaccharide (LPS) during aquatic blooms, affecting environmental and human health. The putative toxic effects of cyanobacterial LPS on brain microglia, a glial cell type that constitutes the main leukocyte-dependent source of reactive oxygen species in the central nervous system, are presently unknown. We tested the hypothesis that in vitro concentration- and time-dependent exposure to M. aeruginosa LPS strain UTCC 299 would activate rat microglia and the concomitant generation of superoxide anion (O2⁻). After a 17-h exposure of microglia to M.aeruginosa LPS, the following concentration-dependent responses were observed: 0.1-100 ng/ml M. aeruginosa LPS enhanced O2⁻ generation, with limited inflammatory mediator generation; 1000-10,000 ng/ml M. aeruginosa LPS caused thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and macrophage inflammatory protein-2 (MIP-2/CXCL2) release, concurrent with maximal O2⁻ generation; 100,000 ng/mL M. aeruginosa LPS deactivated O2⁻ production but maintained elevated levels of TXB2, MMP-9, tumor necrosis factor-α (TNF-α), interleukin 1-α (IL-1α), and interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α/CCL3), and MIP-2/CXCL2, with concomitant lactic dehydrogenase release. Although M. aeruginosa LPS was consistently less potent than Escherichia coli LPS, with the exception of O2⁻, TXB2, and MCP-1/CCL2 generation, it was more efficacious because higher levels of MMP-9, TNF-α, IL-1α, IL-6, MIP-1α/CCL3, and MIP-2/CXCL2 were produced. Our in vitro studies suggest that one or more of the inflammatory mediators released during M. aeruginosa LPS stimulation of microglia may play a critical role in the subsequent ability of microglia to generate O2⁻. To our knowledge, this is the first experimental evidence that LPS isolated from a M. aeruginosa strain, can activate brain microglia in vitro, as well as the release of O2⁻, and other inflammatory mediators hypothesized to be involved in neuroinflammation and neurodegeneration.


Assuntos
Quimiocinas/metabolismo , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Microcystis/química , Microglia/efeitos dos fármacos , Superóxidos/metabolismo , Tromboxano B2/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Microglia/enzimologia , Microglia/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Proc Natl Acad Sci U S A ; 107(28): 12634-9, 2010 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-20616035

RESUMO

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Anilina , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Aurora Quinase B , Aurora Quinases , Inibidores Enzimáticos/uso terapêutico , Masculino , Camundongos , Neoplasias/genética , Proteínas Serina-Treonina Quinases , Sulfonamidas
15.
Trends Pharmacol Sci ; 31(6): 255-65, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20363514

RESUMO

The global marine pharmaceutical pipeline consists of three Food and Drug Administration (FDA) approved drugs, one EU registered drug, 13 natural products (or derivatives thereof) in different phases of the clinical pipeline and a large number of marine chemicals in the preclinical pipeline. In the United States there are three FDA approved marine-derived drugs, namely cytarabine (Cytosar-U((R)), Depocyt((R))), vidarabine (Vira-A((R))) and ziconotide (Prialt((R))). The current clinical pipeline includes 13 marine-derived compounds that are either in Phase I, Phase II or Phase III clinical trials. Several key Phase III studies are ongoing and there are seven marine-derived compounds now in Phase II trials. The preclinical pipeline continues to supply several hundred novel marine compounds every year and those continue to feed the clinical pipeline with potentially valuable compounds. From a global perspective the marine pharmaceutical pipeline remains very active, and now has sufficient momentum to deliver several additional compounds to the marketplace in the near future; this review provides a current view of the pipeline.


Assuntos
Produtos Biológicos/uso terapêutico , Descoberta de Drogas/métodos , Drogas em Investigação/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Biologia Marinha , Estados Unidos , United States Food and Drug Administration
16.
Mol Cancer Ther ; 9(3): 653-60, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20197394

RESUMO

The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of <30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC(50) of 1.25 and 2 mumol/L after 72 h of treatment, respectively. The phosphorylation of PDGFRbeta, c-KIT, and extracellular signal-regulated kinases was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRbeta and c-KIT pathways.


Assuntos
Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sarcoma de Ewing/patologia , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Sarcoma de Ewing/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biochem Pharmacol ; 78(5): 440-8, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19393227

RESUMO

Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt (ziconotide, omega-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis) (trabectedin, ET-743) an antitumor agent scovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.


Assuntos
Produtos Biológicos/isolamento & purificação , Biologia Marinha , Produtos Biológicos/farmacologia , Aprovação de Drogas/legislação & jurisprudência , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Estados Unidos , United States Food and Drug Administration
18.
Blood ; 113(17): 4052-62, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19144991

RESUMO

To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869-mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Subtoxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Feminino , Humanos , Indazóis/farmacologia , Proteínas Inibidoras de Apoptose , Leucemia Mieloide Aguda/genética , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Compostos de Fenilureia/farmacologia , Fator de Transcrição STAT3/genética , Sesquiterpenos/farmacologia , Especificidade por Substrato , Survivina , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/metabolismo
19.
J Hepatol ; 49(6): 985-97, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18930332

RESUMO

BACKGROUND/AIMS: Receptor tyrosine kinase inhibitors (RTKIs) and mTOR inhibitors are potential novel anticancer therapies for HCC. We hypothesized that combination targeted on distinctive signal pathways would provide synergistic therapeutics. METHODS: ABT-869, a novel RTKI, and rapamycin were investigated in HCC pre-clinical models. RESULTS: Rapamycin, but not ABT-869, inhibited in vitro growth of Huh7 and SK-HEP-1 HCC cells in a dose dependant manner. However, in subcutaneous Huh7 and SK-HEP-1 xenograft models, either ABT-869 or rapamycin can significantly reduce tumor burden. Combination treatment reduced the tumors to the lowest volume (95+/-20mm(3)), and was significantly better than single agent treatment (p<0.05). Immunohistochemical staining of tumor shows that ABT-869 potently inhibits VEGF in HCC in vivo. In addition, the MAPK signaling pathway has been inhibited by significant inhibition of phosphorylation of p44/42 MAP kinase by ABT-869 in vivo. Rapamycin inhibits phosphorylation of p70 S6 kinase and 4E-BP-1, downstream targets of mTOR, and decreases VEGF. Combination treatment showed synergistic effect on expression levels of p27 in vivo. Dramatic inhibition of neo-angiogenesis by ABT-869 was also demonstrated. CONCLUSIONS: HCC could potentially be treated with the combination treatment of ABT-869 and rapamycin. Clinical trials on combination therapy are warranted.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Imunossupressores/farmacologia , Indazóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Sirolimo/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Gordura Subcutânea , Serina-Treonina Quinases TOR , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Med Chem ; 51(13): 3777-87, 2008 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-18557606

RESUMO

7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).


Assuntos
Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Edema/tratamento farmacológico , Edema/enzimologia , Feminino , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Compostos de Fenilureia/química , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/química , Pirazóis/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/química , Relação Estrutura-Atividade , Ureia/química , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/enzimologia
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