RESUMEN
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
Asunto(s)
Alquinos/metabolismo , Compuestos de Anilina/metabolismo , Receptores ErbB/metabolismo , Modelos Moleculares , Pirimidinas/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Femenino , Isatina/análogos & derivados , Isatina/metabolismo , Espectrometría de Masas , Ratones , Ratones SCID , Estructura Molecular , Pirimidinas/toxicidad , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tiofenos/antagonistas & inhibidores , Animales , Ciclo Celular , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Mitosis , Modelos Químicos , Conformación Molecular , Proteínas Serina-Treonina Quinasas/química , Proteínas Proto-Oncogénicas/química , Tiofenos/química , Quinasa Tipo Polo 1RESUMEN
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Asunto(s)
Compuestos de Anilina/síntesis química , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Receptores ErbB/metabolismo , Inhibidores de Crecimiento/administración & dosificación , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Humanos , Ratones , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Receptor ErbB-2/metabolismoRESUMEN
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Asunto(s)
Antineoplásicos/química , Receptores ErbB/antagonistas & inhibidores , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Ratones , Farmacocinética , Pirimidinas/síntesis química , Pirrolidinas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.