RESUMO
The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.
Assuntos
Indóis/química , Indolizidinas/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Compostos de Espiro/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazolinas/química , Indóis/uso terapêutico , Indóis/toxicidade , Indolizidinas/uso terapêutico , Indolizidinas/toxicidade , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/química , Compostos de Espiro/uso terapêutico , Compostos de Espiro/toxicidade , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , para-Aminobenzoatos/químicaRESUMO
PURPOSE: Gamunex 10% (Talecris Biotherapeutics, Research Triangle Park, NC), a commercially available preparation of pooled human immunoglobulin G, has been proposed as an antitoxin therapy against bacterial toxins released in infectious endophthalmitis. Its biocompatibility with two commonly used intraocular infusion fluids was evaluated to determine feasibility of its clinical application in endophthalmitis treatment. METHODS: Gamunex 10% was mixed with BSS or BSS Plus (Alcon Laboratories, Fort Worth, TX) such that it constituted a range of 1.25%-50% by volume. Osmolality, pH, optical density, and ionic strength were measured across this range of concentrations. RESULTS: The amount of pH reduction with increasing concentrations of Gamunex 10% was similar for both BSS and BSS Plus. In BSS Plus, solutions containing up to 20% by volume of Gamunex 10% remained at near-physiologic pH (â¼7.0 or above). No physiologically significant changes in osmolality or optical density measurements that would be anticipated to have profound physiological effects were observed at any of the measured concentrations, nor was there visual evidence of tubidity/precipitation. A gradual increase in ionic strength was observed with increasing concentrations of Gamunex 10%. CONCLUSIONS: Potentially therapeutic mixtures of Gamunex 10% in 2 commonly used intraocular infusion fluids, BSS and BSS Plus, showed no evidence of bioincompatibility when the solutions were evaluated for changes in osmolality, pH, ionic strength, aggregation, or precipitation.
Assuntos
Acetatos/química , Bicarbonatos/química , Caprilatos/química , Glutationa/química , Imunoglobulinas Intravenosas/química , Minerais/química , Cloreto de Sódio/química , Acetatos/administração & dosagem , Acetatos/uso terapêutico , Bicarbonatos/administração & dosagem , Bicarbonatos/uso terapêutico , Caprilatos/administração & dosagem , Caprilatos/uso terapêutico , Precipitação Química , Combinação de Medicamentos , Incompatibilidade de Medicamentos , Endoftalmite/imunologia , Endoftalmite/microbiologia , Endoftalmite/terapia , Glutationa/administração & dosagem , Glutationa/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Minerais/administração & dosagem , Minerais/uso terapêutico , Soluções Oftálmicas , Concentração Osmolar , Cloreto de Sódio/administração & dosagem , Cloreto de Sódio/uso terapêuticoRESUMO
PURPOSE: This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo. METHODS: The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established. RESULTS: R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration. CONCLUSIONS: R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties.