RESUMEN
CA1A2X peptidomimetics containing a modified proline at position A2 were prepared and evaluated for their ability to inhibit farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) in enzymatic and cell-based assays. These compounds inhibited farnesylation of H-ras in vitro in the high nanomolar to low micromolar IC50 range.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hidroxiprolina/química , Prolina/análogos & derivados , Prolina/síntesis química , Células 3T3 , Transferasas Alquil y Aril/metabolismo , Animales , Fenómenos Químicos , Química Física , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Genes ras/efectos de los fármacos , Ratones , Prolina/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of peptidomimetics based on a hydroxyproline scaffold was prepared and evaluated for inhibition of farnesyltransferase and geranylgeranyltransferase I in both enzymatic and cell-based assays. A number of analogs were potent and selective inhibitors of FTase, while one compound (22) was nonselective in the enzymatic assays but eight-fold selective for inhibition of GGTase in the cellular assay (IC50 = 0.39 microM).
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hidroxiprolina/química , Péptidos/química , Células 3T3/efectos de los fármacos , Animales , Diseño de Fármacos , Concentración 50 Inhibidora , Metionina/análogos & derivados , Metionina/farmacología , Ratones , Imitación Molecular , Relación Estructura-ActividadRESUMEN
It has recently been reported that Ki-Ras protein can be modified in vitro by farnesylation or geranylgeranylation. However, a previous analysis of Ki-Ras prenylation in vivo found only farnesylated Ki-Ras. In this report it is shown that under normal conditions, Ki-Ras is farnesylated in vivo and when cells are treated with the farnesyl transferase inhibitors B956 or B957, farnesylation is inhibited and Ki-Ras becomes geranylgeranylated in a dose dependent manner. These results have strong implications in the design of anticancer drugs based on inhibition of prenylation.
