RESUMEN
Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.
Asunto(s)
Antirreumáticos/síntesis química , Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/fisiología , FN-kappa B/antagonistas & inhibidores , Nitrilos/síntesis química , Propionatos/síntesis química , Administración Oral , Animales , Animales Modificados Genéticamente , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antirreumáticos/química , Antirreumáticos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Línea Celular , Creatina Quinasa/metabolismo , Cristalografía por Rayos X , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Luciferasas/genética , Ratones , FN-kappa B/biosíntesis , FN-kappa B/genética , Nitrilos/química , Nitrilos/farmacología , Propionatos/química , Propionatos/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Pirazoles/uso terapéutico , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/inmunología , Enfermedad Crónica , Humanos , Ligandos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
Asunto(s)
Antiinflamatorios/síntesis química , Artritis Reumatoide/tratamiento farmacológico , Indazoles/síntesis química , Fenoles/síntesis química , Receptores de Estrógenos/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Línea Celular , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Humanos , Indazoles/química , Indazoles/farmacología , Ligandos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , FN-kappa B/biosíntesis , FN-kappa B/genética , Fenoles/química , Fenoles/farmacología , Ratas , Ratas Endogámicas Lew , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
ErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients.
Asunto(s)
Antineoplásicos/farmacología , Paclitaxel/farmacología , Quinolinas/farmacología , Interferencia de ARN , Neoplasias de la Mama , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Genes Relacionados con las Neoplasias , Estudio de Asociación del Genoma Completo , Humanos , Lentivirus/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor ErbB-2/biosíntesis , Proteínas Recombinantes/biosíntesis , Transducción de SeñalRESUMEN
Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.
Asunto(s)
FN-kappa B/antagonistas & inhibidores , Pirazoles/metabolismo , Pirazoles/farmacología , Receptores de Estrógenos/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Línea Celular , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Antígeno HLA-B27/genética , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Pirazoles/química , Ratas , Útero/efectos de los fármacos , Útero/metabolismoRESUMEN
A well-established model of bowel inflammation is the HLA-B27 transgenic rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens have previously been shown to modulate the immune system, and both estrogen receptors (ERalpha and ERbeta) are present in the intestine and cells of the immune system. Therefore, the ability of estrogen to ameliorate disease progression in the HLA-B27 transgenic rat was determined. HLA-B27 transgenic rats with chronic diarrhea were treated with 17alpha-ethynyl-17beta-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores of the degree of ulceration, inflammatory cell infiltration, fibrosis, and lesion depth of the colon were also improved by EE treatment. Because neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase (MPO) activity was measured. MPO levels were reduced by 80% by EE treatment. Cotreatment with the pure ER antagonist ICI-182780 (ICI) blocked the effects of EE on stool character, MPO activity, and histology scores, strongly suggesting that the activity of EE is mediated through ER. Mast cell proteases can promote neutrophil infiltration, and gene expression analysis demonstrated that mast cell protease 1, 3, and 4 mRNA were all decreased in colons from estrogen-treated rats. In addition, a direct effect of estrogen on bone marrow-derived mast cell activity was demonstrated, suggesting that ER-mediated inactivation of mast cells may contribute to the improvement in the clinical sign and histological scores in this model.