ABSTRACT
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Imidazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pteridines/chemical synthesis , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HT29 Cells , Heterografts , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Molecular Structure , Pteridines/chemistry , Pteridines/pharmacology , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
OBJECTIVE: To analyze the clinical characteristics, 5-year survival, and prognostic factors of squamous cell carcinoma (SCC) of the external and middle ear. METHODS: A multi institutional study. Ninety five cases of patients from 10 institutions were reviewed on their age and sex distribution, initial complaints, stages, tumor locations, treatments, and outcomes. Prognostic factors were discussed based on the Pittsburgh staging system. RESULTS: This disease seems to appear in the elderly with a peak age of 50-69 years. Males appear to be more predisposed than females with an odd ratio of 1.7. The initial complaints were not typical, while 12.6% of patients presented a history of recurrent otitis externa or chronic otitis media. Regional metastasis was recognized in 13.7% of patients, while no distant metastasis was confirmed. SCC located in the external ear could be detected in an earlier stage than that in the middle ear. The overall 5-year survival was 66.8% in total, and decreased significantly with stage. SCC in stages I and II was susceptible to each therapeutic strategy with a 5-year survival of 100%. Operation combined with radiotherapy and/or chemotherapy was the major treatment for stages III and IV SCC, while radiotherapy and chemotherapy were applied mainly for those who had been considered inappropriate for operation. The overall survival was 67.2% for stage III and 29.5% for stage IV, and operation with pathologically tumor free margin could improve the survival to 72.7% when combined with radio- and chemotherapy. Stage, completeness of operation with tumor free margin, recurrence, and metastasis have significant influence on survival. CONCLUSION: Local infiltration seems to be the main behavior of SCC in the external and middle ear. Early diagnosis and treatment were important because SCC in the earlier stage is susceptible to be cured. For tumors of advanced stage, operation should be performed with pathologically tumor free margin, and operation combined with radiotherapy and chemotherapy could improve the survival. Tumor stage adds more influence on survival than its location. Recurrence and metastasis mainly occur in advanced stages and result in a poor survival.
