RESUMEN
Reported herein are the design, synthesis, and Grb2 SH2 domain-binding affinities of several phosphoryl-mimicking groups displayed within the context of a conformationally constrained macrocyclic platform. With use of surface plasmon resonance techniques, single-digit nanomolar affinities were exhibited by phosphonic acid and malonyl-containing diacidic phosphoryl mimetics (for 4h and 4g, K(D) = 1.47 and 3.62 nM, respectively). Analogues containing monoacidic phosphoryl mimetics provided affinities of K(D) = 16-67 nM. Neutral phosphoryl-mimicking groups did not show appreciable binding.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/química , Compuestos Macrocíclicos/síntesis química , Organofosfatos/química , Dominios Homologos src , Sitios de Unión , Unión Competitiva , Ensayo de Inmunoadsorción Enzimática , Proteína Adaptadora GRB2 , Compuestos Macrocíclicos/química , Imitación Molecular , Relación Estructura-Actividad , Resonancia por Plasmón de SuperficieRESUMEN
Germline missense mutations in the tyrosine kinase domain of the hepatocyte growth factor/scatter factor (HGF/SF) receptor, c-Met, are thought to be responsible for hereditary papillary renal carcinoma (HPRC) type 1, a form of human kidney cancer. In addition to extensive linkage analysis of HPRC families localizing the HPRC type 1 gene within chromosome 7, the demonstration that individual c-Met mutations reconstituted in cultured cells display enhanced and dysregulated kinase activity, and confer cell transformation and tumorigenicity in mice, solidifies this conclusion. Our prior knowledge of HGF/SF biology and c-Met signaling enabled rapid progress in unraveling the molecular pathogenesis of HPRC type 1, and in laying the framework for the development of novel therapeutics for the treatment of this cancer. At the same time, the study of HPRC type 1 has refined our appreciation of the oncogenic potential of c-Met signaling, and challenges our current understanding of HGF/SF and c-Met function in health and disease.
Asunto(s)
Carcinoma Papilar/genética , Neoplasias Renales/genética , Proteínas Proto-Oncogénicas c-met/genética , Carcinoma Papilar/clasificación , Línea Celular Tumoral , Humanos , Neoplasias Renales/clasificación , MutaciónRESUMEN
Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Proteína Adaptadora GRB2/antagonistas & inhibidores , Animales , Sistemas de Liberación de Medicamentos , Proteína Adaptadora GRB2/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Fluorescence labeling has become a general technique for studying the intracellular accumulation and localization of exogenously administered materials. Reported herein is a low nanomolar affinity Grb2 SH2 domain-binding antagonist that utilizes the environmentally-sensitive nitrobenzoxadiazole (NBD) fluorophore as a naphthyl replacement. This novel agent should serve as a useful tool to visualize the actions of this class of Grb2 SH2 domain-binding antagonists in whole cell systems.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Colorantes Fluorescentes/química , Oxadiazoles/química , Péptidos/química , Péptidos/farmacología , Dominios Homologos src/efectos de los fármacos , Unión Competitiva , Diseño de Fármacos , Colorantes Fluorescentes/síntesis química , Proteína Adaptadora GRB2 , Ligandos , Conformación Molecular , Imitación Molecular , Oxadiazoles/síntesis química , Unión Proteica/efectos de los fármacos , Coloración y Etiquetado/métodos , Relación Estructura-ActividadRESUMEN
Prostate cancer detection is a rare occurrence in patients with Klinefelter syndrome, in whom chronically low circulating androgen levels are common findings. Administration of exogenous testosterone has increasingly been used to treat young adolescents diagnosed with Klinefelter syndrome and documented androgen deficiency. Although testosterone replacement in adult patients has been associated with prostatic enlargement, it remains unknown whether chronic supplementation of exogenous testosterone to pubescent males with hypogonadism results in early prostate carcinogenesis. We report a first case of prostate cancer in a patient with Klinefelter syndrome who had undergone long-term testosterone replacement therapy since childhood for chronically depressed levels of testosterone.