RESUMEN
Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase exerts antiproliferative and cytotoxic effects in vitro and in vivo and has been shown to act synergistically with different cancer therapeutic agents. The cytotoxic and cytostatic effects of ranpirnase are the consequence of tRNA degradation that results in the disruption of protein translation and the induction of programmed cell death (apoptosis). Ranpirnase has been shown to target malignant cells both in human cancer cell lines and in animal models, and has demonstrated efficacy in the treatment of several human cancers in clinical studies. Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Mesotelioma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Ribonucleasas/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Humanos , Rana pipiensRESUMEN
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Oximas/farmacología , Pirimidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Oximas/síntesis química , Oximas/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.
