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1.
Bioorg Med Chem Lett ; 30(7): 126955, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035698

RESUMO

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

2.
J Med Chem ; 62(22): 10456-10465, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31724863

RESUMO

The APJ receptor and its endogenous peptidic ligand apelin have been implicated as important modulators of cardiovascular function, and APJ receptor agonists may be beneficial in the treatment of heart failure. In this article, we describe the discovery of a series of biphenyl acid derivatives as potent APJ receptor agonists. Following the identification of initial high-throughput screen lead 2, successive optimization led to the discovery of lead compound 15a. Compound 15a demonstrated comparable in vitro potency to apelin-13, the endogenous peptidic ligand for the APJ receptor. In vivo, compound 15a demonstrated a dose-dependent improvement in the cardiac output in male Sprague Dawley rats with no significant changes in either mean arterial blood pressure or heart rate, consistent with the hemodynamic profile of apelin-13 in an acute pressure volume loop model.

3.
Nat Chem ; 11(12): 1113-1123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31659311

RESUMO

A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small-molecule/protein interactions in human cells. Excavating clear structure-activity relationships from these 'ligandability' maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or 'enantioprobes', we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into fully functionalized fragment libraries provides a robust and streamlined method to discover ligandable proteins in cells.

4.
ACS Med Chem Lett ; 10(6): 911-916, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223447

RESUMO

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.

5.
J Med Chem ; 62(16): 7400-7416, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31246024

RESUMO

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

6.
Anal Biochem ; 568: 41-50, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605634

RESUMO

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/farmacocinética , Peptídeos/análise , Animais , Cromatografia Líquida , Cães , Ensaio de Imunoadsorção Enzimática , Hemodinâmica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
7.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034599

RESUMO

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

8.
Cell ; 168(3): 527-541.e29, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28111073

RESUMO

Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.


Assuntos
Descoberta de Drogas/métodos , Proteômica/métodos , Adipócitos/citologia , Diferenciação Celular , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Humanos , Hidrolases/química , Ligantes , Proteínas de Membrana/antagonistas & inibidores , Oxirredutases/química , Ligação Proteica , Receptores de Progesterona/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas
9.
Sci Transl Med ; 9(371)2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053157

RESUMO

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.


Assuntos
Anticorpos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Receptores de Trombina/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/metabolismo , Cobaias , Células HEK293 , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Domínios Proteicos , Receptor PAR-1/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombina/química , Trombose , Resultado do Tratamento
10.
Anal Biochem ; 501: 48-55, 2016 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-26925857

RESUMO

Monoacylglycerol acyltransferase 2 (MGAT2) is a membrane-bound lipid acyltransferase that catalyzes the formation of diacylglycerol using monoacylglycerol and fatty acyl CoA as substrates. MGAT2 is important for intestinal lipid absorption and is an emerging target for the treatment of metabolic diseases. In the current study, we identified and characterized four classes of novel MGAT2 inhibitors. We established both steady state and kinetic binding assay protocols using a novel radioligand, [(3)H]compound A. Diverse chemotypes of MGAT2 inhibitors were found to compete binding of [(3)H]compound A to MGAT2, indicating the broad utility of [(3)H]compound A for testing various classes of MGAT2 inhibitors. In the dynamic binding assays, the kinetic values of MGAT2 inhibitors such as Kon, Koff, and T1/2 were systematically defined. Of particular value, the residence times of inhibitors on MGAT2 enzyme were derived. We believe that the identification of novel classes of MGAT2 inhibitors and the detailed kinetic characterization provide valuable information for the identification of superior candidates for in vivo animal and clinical studies. The current work using a chemical probe to define inhibitory kinetics can be broadly applied to other membrane-bound acyltransferases.


Assuntos
Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Ensaios Enzimáticos/métodos , Inibidores Enzimáticos/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Humanos , Ligantes , Camundongos , Ligação Proteica/efeitos dos fármacos , Ensaio Radioligante/métodos , Ratos , Proteínas Recombinantes/metabolismo
11.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
12.
J Lipid Res ; 56(3): 747-53, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25598079

RESUMO

To demonstrate monoacylglycerol acyltransferase 2 (MGAT2)-mediated enzyme activity in a cellular context, cells of the murine secretin tumor cell-1 line of enteroendocrine origin were used to construct human MGAT2-expressing recombinant cell lines. Low throughput and utilization of radiolabeled substrate in a traditional TLC technique were circumvented by development of a high-resolution LC/MS platform. Monitoring incorporation of stable isotope-labeled D31-palmitate into diacylglycerol (DAG) allowed selective tracing of the cellular DAG synthesis activity. This assay format dramatically reduced background interference and increased the sensitivity and the signal window compared with the TLC method. Using this assay, several MGAT2 inhibitors from different chemotypes were characterized. The described cell-based assay adds a new methodology for the development and evaluation of MGAT2 inhibitors for the treatment of obesity and type 2 diabetes.


Assuntos
Bioensaio/métodos , Diglicerídeos/biossíntese , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Camundongos , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Obesidade/genética , Ácido Palmítico/metabolismo
13.
J Lipid Res ; 55(7): 1366-74, 2014 07.
Artigo em Inglês | MEDLINE | ID: mdl-24755647

RESUMO

A method is described that allows noninvasive identification and quantitative assessment of lipid classes present in sebaceous excretions in rodents. The method relies on direct high-field proton NMR analysis of common group lipid protons in deuterated organic solvent extracts of fur. Extracts from as little as 15 mg of fur from rat, mouse, and hamster provided acceptable results on a 600 MHz NMR equipped with a cryogenically cooled proton-observe probe. In rats, sex- and age-related differences in lipid composition are larger than differences in fur collected from various body regions within an individual and much larger than interanimal differences in age- and sex-matched specimens. The utility of this method to noninvasively monitor drug-induced sebaceous gland atrophy in rodents is demonstrated in rats dosed with a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In this model, a 35% reduction in sebum lipids, extracted from fur, was observed. Finally, structural elucidation of cholesta-7,24-dien-3ß-ol ester as the most prominent, previously unidentified sebum sterol ester in male Syrian hamsters is described. The utility of this method for drug and cosmetic safety and efficacy assessment is discussed.


Assuntos
Pelo Animal/metabolismo , Inibidores Enzimáticos/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças das Glândulas Sebáceas/metabolismo , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Masculino , Mesocricetus , Camundongos , Ressonância Magnética Nuclear Biomolecular , Ratos Sprague-Dawley , Doenças das Glândulas Sebáceas/induzido quimicamente , Estearoil-CoA Dessaturase/metabolismo
15.
J Med Chem ; 56(4): 1704-14, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23368907

RESUMO

Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.


Assuntos
Fibrinolíticos/síntese química , Compostos de Fenilureia/síntese química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Piridinas/síntese química , Ureia/análogos & derivados , Animais , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/tratamento farmacológico , Tempo de Sangramento , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Células HEK293 , Humanos , Masculino , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Trombose/sangue , Trombose/tratamento farmacológico , Ureia/síntese química , Ureia/química , Ureia/farmacologia
17.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
18.
Bioorg Med Chem Lett ; 21(24): 7516-21, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22041058

RESUMO

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 µM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.


Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Piperidonas/química , Inibidores de Serino Proteinase/química , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Fator Xa/metabolismo , Humanos , Lactamas/química , Conformação Molecular , Piperidonas/síntese química , Piperidonas/farmacologia , Estrutura Terciária de Proteína , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
19.
Mol Cancer Res ; 9(11): 1551-61, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21954435

RESUMO

Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that desaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Estearoil-CoA Dessaturase/biossíntese , Estearoil-CoA Dessaturase/deficiência , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Transfecção
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