RESUMEN
The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations <1 microM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B(2) as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with K(i) values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B(2) in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Quinolinas/síntesis química , Quinolonas/síntesis química , Quinonas/síntesis química , Fosfatasas cdc25/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Moleculares , Quinolinas/química , Quinolinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Quinonas/química , Quinonas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Fosfatasas cdc25/metabolismoRESUMEN
OBJECTIVE: To measure long-term provider (physicians and physician's assistants) health maintenance compliance 4 years after the completion of a grant-funded project to improve provider compliance by using a computer-based health maintenance tracking system. DESIGN: Cross-sectional comparison of provider health maintenance compliance for patients receiving computer-based health maintenance tracking in 1992 and 1996. SETTING: Rural, multiple-office, nonprofit, fee-for-service family practice. MAIN OUTCOME MEASURES: Overall provider compliance with the common elements of the health maintenance protocols in 1992 and 1996. Provider compliance with specific, individual preventive interventions was compared. RESULTS: Overall provider compliance was 83% in 1996, compared with 80% in 1992. This difference was statistically significant (P = .05) but not clinically significant. Provider compliance was significantly higher in 1996 for 3 procedures: blood pressure determination, tetanus-diphtheria immunization, and weight. It was unchanged for 5 procedures: clinical breast examination, mammography, Papanicolaou smears, cholesterol determination, and fecal occult blood testing for colon cancer. Provider compliance with obtaining a history of tobacco use declined. CONCLUSION: Improvements in provider health maintenance compliance associated with installation of a computer-based health maintenance tracking system were maintained 4 years after cessation of the formal research intervention.