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1.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-234402

RESUMO

<p><b>OBJECTIVE</b>To identify the disease-causing gene in a four-generation Chinese family with 9 members affected with primary congenital lymphoedema (PCL, also known as Milroy disease).</p><p><b>METHODS</b>Linkage analysis was performed with a few microsatellite markers flanking the candidate genetic loci for PCL, including 3 known genes associated with autosomal dominant PCL. For mutation analysis, VEGFR3 gene was sequenced with DNA from the proband. Direct DNA sequencing of exon 25 of the VEGFR3 gene was performed in all family members.</p><p><b>RESULTS</b>The disease gene in the family was mapped to chromosome 5q35.3 with a maximum Lod score of 2.07. Direct DNA sequencing of VEGFR3 gene revealed a heterozygous C to T transition at nucleotide 3341, resulting in p.Pro1114Leu mutation. The p.Pro1114Leu mutation co-segregated with all affected individuals in the family.</p><p><b>CONCLUSION</b>This study identified a C3341T (p.Pro1114Leu) mutation in the VEGFR3 gene in a Chinese family with PCL, provided evidence that VEGFR3 mutation can cause PCL in Chinese.</p>


Assuntos
Humanos , Substituição de Aminoácidos , Povo Asiático , Genética , Catarata , Genética , Loci Gênicos , Escore Lod , Linfedema , Genética , Repetições de Microssatélites , Genética , Mutação , Mutação Puntual , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , Genética
2.
Future Med Chem ; 1(6): 1153-71, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21425998

RESUMO

BACKGROUND: The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. RESULTS: Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily. CONCLUSION: OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirazinas/síntese química , Pirazinas/química , Pirazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/química , Receptor de Insulina/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 68(20): 8322-32, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18922904

RESUMO

Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic growth inhibition has been reported for combined blockade of EGFR and IGF-IR. However, in preclinical models, only a subset of tumors exhibit high sensitivity to this combination, highlighting the potential need for patient selection to optimize clinical efficacy. Herein, we have characterized the molecular basis for cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide biomarkers that seem to differentiate response. We find for epithelial, but not for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in vitro and growth regression in vivo upon combined blockade of both receptors. We identified two molecular aspects contributing to synergy: (a) inhibition of EGFR or IGF-IR individually promotes activation of the reciprocal receptor; (b) inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. Mechanistically, we find that inhibition of the MAPK pathway circumvents a negative feedback loop imposed on the IGF-IR- insulin receptor substrate 1 (IRS-1) signaling complex, a molecular scenario that parallels the negative feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed IGF-IR signaling. Collectively, these data show that resistance to inhibition of MEK, mTOR, and EGFR is associated with enhanced IGF-IR-directed Akt signaling, where all affect feedback loops converging at the level of IRS-1.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Imidazóis/farmacologia , Pirazinas/farmacologia , Quinazolinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Receptores ErbB/fisiologia , Cloridrato de Erlotinib , Retroalimentação Fisiológica , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos
4.
EMBO J ; 27(14): 1985-94, 2008 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-18566589

RESUMO

The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.


Assuntos
Receptor IGF Tipo 1/química , Sítios de Ligação , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Humanos , Imidazóis/farmacologia , Mutação , Fosforilação , Pirazinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo
5.
Bioorg Med Chem ; 16(3): 1359-75, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17983756

RESUMO

A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Quinolinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Glicemia/metabolismo , Linhagem Celular , Cães , Feminino , Humanos , Imidazóis/química , Insulina/sangue , Ligantes , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirazinas/química , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Cancer Ther ; 6(8): 2158-67, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17671083

RESUMO

Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC(50) of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II-driven human tumor model.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Comunicação Autócrina/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/farmacocinética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/química , Pirazinas/farmacocinética , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biochem J ; 363(Pt 2): 395-401, 2002 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11931670

RESUMO

Phospholipase C-gamma1 (PLC-gamma1) activation has been reported to enhance cell survival during the cellular response to oxidative stress. We studied the role of protein kinase C (PKC) pathways in mediating PLC-gamma1 survival signalling in oxidative stress by using mouse embryonic fibroblasts genetically deficient in PLC-gamma1 (Plcg1(-/-)) and its wild type (Plcg1(+/+)). PLC-gamma1 was activated by H(2)O(2) treatment in a dose- and time-dependent manner. Activation of PKC was also markedly increased in both cell lines treated with H(2)O(2) (1-5 mM), but with low doses (50-200 microM), PKC activation was considerably decreased in Plcg1(-/-) cells. After treatment with H(2)O(2), PKC-dependent phosphorylation of Bcl-2 and cell viability of Plcg1(-/-) cells decreased dramatically and caspase-3-like activity increased significantly compared with that of the wild-type cells. Furthermore, pretreatment of Plcg1(+/+) cells with PKC-specific inhibitor decreased levels of PKC-dependent Bcl-2 phosphorylation, enhanced caspase-3 activity and their sensitivity to H(2)O(2). On the contrary, treatment of Plcg1(-/-) cells with PKC-specific activator increased the Bcl-2 phosphorylation, decreased caspase-3 activity and improved their survival. These results suggest that PLC-gamma1 mediates survival signalling in oxidative-stress response by PKC-dependent phosphorylation of Bcl-2 and inhibition of caspase-3.


Assuntos
Sobrevivência Celular/fisiologia , Isoenzimas/metabolismo , Estresse Oxidativo/fisiologia , Proteína Quinase C/metabolismo , Fosfolipases Tipo C/metabolismo , Animais , Caspase 3 , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Isoenzimas/deficiência , Isoenzimas/genética , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfolipase C gama , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fosfolipases Tipo C/deficiência , Fosfolipases Tipo C/genética
10.
J Biochem ; 131(2): 207-12, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11820933

RESUMO

The consequences of heat-induced phospholipase C-gamma1 (PLC-gamma1) phosphorylation are not known. We investigated the role of PLC-gamma1 activation and its downstream targets during the cellular response to heat stress using mouse embryonic fibroblasts genetically deficient in PLC-gamma1 (Plcg1 null MEF) and its wild type (wt MEF) as models. Treatment of wt MEF with heat resulted in temperature- and heating duration-dependent tyrosine phosphorylation of PLC-gamma1. HSP70 synthesis and the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal protein kinase (JNK) increased equally following heat treatment in both cell lines. However, heat-induced protein kinase C (PKC) activation was dramatically reduced in Plcg1 null MEF compared with wt MEF. Importantly, the mitochondrial localization of PKCalpha, PKC-dependent phosphorylation of Bcl-2, and cell viability in Plcg1 null MEF following heat treatment, were significantly decreased compared with the wild type. Furthermore, pretreatment with bryostatin-1, a PKC activator, enhanced Bcl-2 phosphorylation and cellular resistance to heat-induced apoptosis in Plcg1 null MEF. Taken together, these results suggest that PLC-gamma1 activation enhances cell survival through the PKC-dependent phosphorylation of Bcl-2 during the cellular response to heat stress.


Assuntos
Sobrevivência Celular/fisiologia , Fibroblastos/metabolismo , Isoenzimas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fosfolipases Tipo C/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática , Proteínas de Choque Térmico HSP70/metabolismo , Temperatura Alta , Immunoblotting , Isoenzimas/deficiência , Isoenzimas/genética , MAP Quinase Quinase 4 , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfolipase C gama , Fosforilação , Transdução de Sinais , Fosfolipases Tipo C/deficiência , Fosfolipases Tipo C/genética , Tirosina/metabolismo
11.
Di Yi Jun Yi Da Xue Xue Bao ; 21(12): 888-889, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-12426156

RESUMO

OBJECTIVE: To investigate the expression of phospholipase C-gamma1(PLC-gamma1) in human fetal tissues. METHODS: Serial sections 5 &mgr;m in thickness were prepared from paraformadehyde-fixed and paraffin-embedded normal human fetal tissues including the cartilage, the cartilage membrane and the muscle tissues. The distribution of PLC-gamma1 expression was examined immunohistochemically in the sections. RESULTS: Immunoreactive PLC-gamma1 was readily detected in the cells of the cartilage, the cartilage membrane and the muscl tissues, which was largely confined within the cytoplasm. CONCLUSION: PLC-gamma1 is essential for the early development and cell proliferation of human embryos.

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