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1.
Int J Mol Sci ; 24(4)2023 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-36834678

RESUMEN

Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be a key risk factor. In particular, mutations in the von Hippel-Lindau gene (Vhl) have attracted a lot of interest since this gene regulates the hypoxia inducible transcription factors HIF-1α and HIF-2α, which in turn drive the transcription of many genes that are important for renal cancer growth and progression, including genes involved in lipid metabolism and signaling. Recent data suggest that HIF-1/2 are themselves regulated by bioactive lipids which make the connection between lipids and renal cancer obvious. This review will summarize the effects and contributions of the different classes of bioactive lipids, including sphingolipids, glycosphingolipids, eicosanoids, free fatty acids, cannabinoids, and cholesterol to renal carcinoma progression. Novel pharmacological strategies interfering with lipid signaling to treat renal cancer will be highlighted.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Lípidos , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética
2.
Immunology ; 160(1): 10-23, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32020584

RESUMEN

Given the critical role that the immune system plays in a multitude of diseases, having a clear understanding of the pharmacology of the immune system is crucial to new drug discovery and development. Here we describe the International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Immunopharmacology (GtoImmuPdb), which connects expert-curated pharmacology with key immunological concepts and aims to put pharmacological data into the hands of immunologists. In the pursuit of new therapeutics, pharmacological databases are a vital resource to researchers through providing accurate information on the fundamental science underlying drug action. This extension to the existing IUPHAR/British Pharmacological Society Guide to Pharmacology supports research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease. To provide a deeper context for how the resource can support research we show data in GtoImmuPdb relating to a case study on the targeting of vascular inflammation.


Asunto(s)
Bases de Datos Farmacéuticas , Desarrollo de Medicamentos , Descubrimiento de Drogas , Sistema Inmunológico/diagnóstico por imagen , Factores Inmunológicos/farmacología , Alergia e Inmunología/educación , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Aterosclerosis/prevención & control , Humanos , Factores Inmunológicos/uso terapéutico , Mediadores de Inflamación/metabolismo , Cooperación Internacional , Terapia Molecular Dirigida/métodos , Investigación Farmacéutica/educación , Farmacología Clínica/educación , Ensayos Clínicos Controlados Aleatorios como Asunto , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sociedades Científicas/organización & administración , Resultado del Tratamiento
3.
J Neurochem ; 153(4): 510-524, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31618458

RESUMEN

Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have not been successful. We hypothesized that molecular profiling in combination with in vitro drug sensitivity testing allows to identify signatures associated with sensitivity or resistance to PI3K/mTOR pathway inhibition. We analyzed the molecular mechanisms determining sensitivity to PI3K/mTOR inhibition using gene silencing or pharmacological target inhibition and proliferation, clonogenicity, or spherogenicity as readouts, in human long-term glioma cell (LTC) lines and glioma-initiating cells (GIC). Cultured glioma cells were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/mTOR antagonist. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3ß) were more sensitive to PQR309. Accordingly, the activity of PQR309 was synergistically enhanced by AKT gene silencing or direct pharmacological AKT inhibition. In vivo studies confirmed the anti-glioma activity of PQR309 alone or in combination with AKT inhibition in the orthotopic LN-229 glioma xenograft model in nude mice. These data justify to explore combined targeted therapy approaches in glioblastoma that aim at down-regulating AKT function to enhance the therapeutic potential of dual PI3K/mTOR inhibitors.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Silenciador del Gen/fisiología , Glioblastoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/farmacología , Animales , Proteínas de Ciclo Celular/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Silenciador del Gen/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Distribución Aleatoria , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
IUBMB Life ; 72(6): 1094-1096, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32441880

RESUMEN

The 10th jubilee conference (IPK2019) took place on September 15-19, 2019 in Warsaw, on the Ochota campus as the IUBMB Focused Meeting entitled "Inhibitors of Protein Kinases. Kinase inhibitors in target biology and disease".


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo
5.
Nucleic Acids Res ; 46(D1): D1091-D1106, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29149325

RESUMEN

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ∼9000 ligands, ∼15 000 binding constants, ∼6000 papers and ∼1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been 'forked' from the well-established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions.


Asunto(s)
Bases de Datos Farmacéuticas , Fenómenos del Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Animales , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Ligandos , Farmacología , Proteínas/efectos de los fármacos
6.
Chimia (Aarau) ; 74(10): 779-783, 2020 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-33115560

RESUMEN

Notch is a key oncogenic pathway in several human cancers and to date, no targeted treatment of Notch activated cancers is available to patients. Therapeutic targeting of Notch has been an unresolved challenge due to severe on-target dose limiting toxicities associated with pan-Notch inhibition by either γ-secretase inhibitors or receptor/ligand targeting MAbs. At Cellestia Biotech, we have identified novel series of small molecule inhibitors of the Notch transcription complex. These molecules act as pan-Notch inhibitors and do not cause toxicities commonly associated with first- and second-generation Notch inhibitors currently tested in the clinic, thus providing a novel and unique opportunity to address a high unmet medical need. Our lead molecule, CB-103 is currently being investigated in Phase-1 dose escalation in cancer patients. Cellestia Biothech is further expanding its medicinal chemistry activities advancing the development of novel molecules for targeting transcription factors in cancer as well as non-cancer indications.


Asunto(s)
Neoplasias , Receptores Notch , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Transducción de Señal
7.
Int J Mol Sci ; 20(22)2019 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-31752127

RESUMEN

The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention.


Asunto(s)
Neoplasias/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Humanos , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Enfermedades Raras/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Serina-Treonina Quinasas TOR/metabolismo
8.
Nucleic Acids Res ; 44(D1): D1054-68, 2016 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-26464438

RESUMEN

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs and their targets in the human genome. Developed by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS), this resource, and its earlier incarnation as IUPHAR-DB, is described in our 2014 publication. This update incorporates changes over the intervening seven database releases. The unique model of content capture is based on established and new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified by UniProtKB IDs. Small molecules are defined by PubChem Compound Identifiers (CIDs); ligand capture also includes peptides and clinical antibodies. We have extended the capture of ligands and targets linked via published quantitative binding data (e.g. Ki, IC50 or Kd). The resulting pharmacological relationship network now defines a data-supported druggable genome encompassing 7% of human proteins. The database also provides an expanded substrate for the biennially published compendium, the Concise Guide to PHARMACOLOGY. This article covers content increase, entity analysis, revised curation strategies, new website features and expanded download options.


Asunto(s)
Bases de Datos Farmacéuticas , Descubrimiento de Drogas , Proteínas/efectos de los fármacos , Ontologías Biológicas , Enfermedad , Genoma Humano , Humanos , Internet , Ligandos , Patentes como Asunto , Fosfotransferasas/antagonistas & inhibidores , Proteínas/genética
9.
Biochim Biophys Acta ; 1861(11): 1840-1851, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27616330

RESUMEN

Breast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine 1-phosphate (S1P) and its binding to cognate receptor subtypes on the cell surface. To investigate the effect of this interaction on the metastatic phenotype, we used the breast cancer cell line MDA-MB-231 and the sublines 4175 and 1833 derived from lung and bone metastases in nude mice, respectively. In both metastatic cell lines expression of the S1P3 receptor was strongly upregulated compared to the parental cells and correlated with higher S1P-induced intracellular calcium ([Ca2+]i), higher cyclooxygenase (COX)-2 and microsomal prostaglandin (PG) E2 synthase expression, and consequently with increased PGE2 synthesis. PGE2 synthesis was decreased by antagonists and siRNA against S1P3 and S1P2. Moreover, in parental MDA-MB-231 cells overexpression of S1P3 by cDNA transfection also increased PGE2 synthesis, but only after treatment with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, indicating reversible silencing of the COX-2 promoter. Functionally, the metastatic sublines showed enhanced migration and Matrigel invasion in adapted Boyden chamber assays, which further increased by S1P stimulation. This response was abrogated by either S1P3 antagonism, COX-2 inhibition or PGE2 receptor 2 (EP2) and 4 (EP4) antagonism, but not by S1P2 antagonism. Our data demonstrate that in breast cancer cells overexpression of S1P3 and its activation by S1P has pro-inflammatory and pro-metastatic potential by inducing COX-2 expression and PGE2 signaling via EP2 and EP4.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular , Dinoprostona/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Regulación hacia Arriba , Neoplasias de la Mama/genética , Calcio/metabolismo , Celecoxib/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lisofosfolípidos/farmacología , Invasividad Neoplásica , Metástasis de la Neoplasia , Prostaglandina-E Sintasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Lisoesfingolípidos/genética , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E/genética , Esfingosina/análogos & derivados , Esfingosina/farmacología , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos
10.
Pharmacol Rev ; 66(4): 918-47, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25026896

RESUMEN

Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.


Asunto(s)
Regulación Alostérica/efectos de los fármacos , Ligandos , Terminología como Asunto , Humanos , Canales Iónicos/metabolismo , Modelos Químicos , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo
11.
FASEB J ; 29(7): 2980-92, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25854701

RESUMEN

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant forms of Parkinson's disease. LRRK2 is a modular, multidomain protein containing 2 enzymatic domains, including a kinase domain, as well as several protein-protein interaction domains, pointing to a role in cellular signaling. Although enormous efforts have been made, the exact pathophysiologic mechanisms of LRRK2 are still not completely known. In this study, we used a chemical genetics approach to identify LRRK2 substrates from mouse brain. This approach allows the identification of substrates of 1 particular kinase in a complex cellular environment. Several of the identified peptides are involved in the regulation of microtubule (MT) dynamics, including microtubule-associating protein (MAP)/microtubule affinity-regulating kinase 1 (MARK1). MARK1 is a serine/threonine kinase known to phosphorylate MT-binding proteins such as Tau, MAP2, and MAP4 at KXGS motifs leading to MT destabilization. In vitro kinase assays and metabolic-labeling experiments in living cells confirmed MARK1 as an LRRK2 substrate. Moreover, we also showed that LRRK2 and MARK1 are interacting in eukaryotic cells. Our findings contribute to the identification of physiologic LRRK2 substrates and point to a potential mechanism explaining the reported effects of LRRK2 on neurite morphology.


Asunto(s)
Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Ratones Noqueados , Microtúbulos/metabolismo , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato
12.
Proc Natl Acad Sci U S A ; 110(47): E4437-45, 2013 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-24191057

RESUMEN

Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type of allosteric inhibitors targeting the Abl myristoyl pocket was shown in preclinical studies to overcome ATP-site inhibitor resistance arising in some patients. Using NMR and small-angle X-ray scattering, we have analyzed the solution conformations of apo Abelson tyrosine kinase (c-Abl) and c-Abl complexes with ATP-site and allosteric inhibitors. Binding of the ATP-site inhibitor imatinib leads to an unexpected open conformation of the multidomain SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on Bcr-Abl. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed, inactivated state. Our data provide detailed insights on the poorly understood combined effect of the two inhibitor types, which is able to overcome drug resistance.


Asunto(s)
Benzamidas/química , Proteínas de Fusión bcr-abl/química , Modelos Moleculares , Complejos Multiproteicos/química , Piperazinas/química , Conformación Proteica , Proteínas Proto-Oncogénicas c-abl/química , Proteínas Proto-Oncogénicas c-abl/metabolismo , Pirimidinas/química , Regulación Alostérica , Benzamidas/metabolismo , Isótopos de Carbono/análisis , Escherichia coli , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Estructura Molecular , Isótopos de Nitrógeno/análisis , Resonancia Magnética Nuclear Biomolecular , Piperazinas/metabolismo , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Pirimidinas/metabolismo , Dispersión del Ángulo Pequeño
13.
Mol Pharmacol ; 87(5): 766-75, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25549667

RESUMEN

Deregulation of protein and lipid kinase activities leads to a variety of pathologies, ranging from cancer inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders. Protein kinases and lipid kinases represent, therefore, an important target for the pharmaceutical industry. In fact, approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases. To date, 30 kinase inhibitors have been approved, which, with few exceptions, are mainly for oncological indications and directed against only a handful of protein and lipid kinases, leaving 70% of the kinome untapped. Despite these successes in kinase drug discovery, the development of kinase inhibitors with outstanding selectivity, identification and validation of driver kinase(s) in diseases, and the emerging problem of resistance to the inhibition of key target kinases remain major challenges. This minireview provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.


Asunto(s)
Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Descubrimiento de Drogas/métodos , Humanos , Neoplasias/metabolismo , Proteínas Quinasas/metabolismo
14.
Cancer Cell ; 12(3): 201-14, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17785202

RESUMEN

To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Sistema de Señalización de MAP Quinasas , Mieloma Múltiple/enzimología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/fisiología , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Apoptosis , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Modelos Biológicos , Mieloma Múltiple/metabolismo , Fosforilación , Interferencia de ARN , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Tirosina/metabolismo
15.
Bioorg Med Chem Lett ; 23(13): 3741-8, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23726034

RESUMEN

Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compounds in inhibiting PI3Kα, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719.


Asunto(s)
Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
16.
Cancer Cell ; 7(2): 129-41, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15710326

RESUMEN

The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/química , Pirimidinas/farmacología , Animales , Benzamidas , Células de la Médula Ósea/citología , Línea Celular , Línea Celular Tumoral , Supervivencia Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Células Madre Hematopoyéticas/citología , Mesilato de Imatinib , Concentración 50 Inhibidora , Ratones , Modelos Biológicos , Modelos Químicos , Mutación , Mycoplasma/metabolismo , Fosforilación , Piperazinas/farmacología , Retroviridae/genética , Factores de Tiempo
17.
Nat Genet ; 36(5): 453-61, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15098032

RESUMEN

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.


Asunto(s)
Linfoma de Burkitt/enzimología , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Familia-src Quinasas/fisiología , Animales , Benzamidas , Linfoma de Burkitt/patología , División Celular/efectos de los fármacos , Quimioterapia Combinada , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Piperazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-hck , Pirimidinas/farmacología , Pirroles/farmacología , Familia-src Quinasas/antagonistas & inhibidores
18.
Br J Pharmacol ; 180 Suppl 2: S289-S373, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-38123154

RESUMEN

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Asunto(s)
Bases de Datos Farmacéuticas , Canales Iónicos , Humanos , Ligandos , Receptores Citoplasmáticos y Nucleares , Receptores Acoplados a Proteínas G
19.
Br J Pharmacol ; 180 Suppl 2: S374-S469, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-38123156

RESUMEN

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Asunto(s)
Bases de Datos Farmacéuticas , Farmacología , Humanos , Ligandos , Canales Iónicos/química , Receptores Acoplados a Proteínas G , Receptores Citoplasmáticos y Nucleares
20.
Br J Pharmacol ; 180 Suppl 2: S241-S288, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-38123155

RESUMEN

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Asunto(s)
Bases de Datos Farmacéuticas , Farmacología , Humanos , Ligandos , Receptores Acoplados a Proteínas G , Canales Iónicos/química , Receptores Citoplasmáticos y Nucleares
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