ABSTRACT
The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.
Subject(s)
CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Proto-Oncogene Proteins , Pyrimidines/chemical synthesis , Adenosine Triphosphate/metabolism , Animals , Cell Division/drug effects , Cell Line , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Insecta/cytology , Kinetics , Models, Molecular , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Liver metastases were discovered in 4 adults during high-dose excretory urography with upper abdominal tomograms. Previous reports in the English literature have noted incidental discovery of hepatic cysts or abscesses during urography, but no documented cases of liver metastases were found. All metastases were visualized as round, lucent, hepatic filling defects during total body opacification. Radiologists performing high dose excretory urography with tomography should routinely scrutinize the hepatogram, because metastases, cysts, or abscesses may be visualized. Final diagnosis of these masses usually depends on additional diagnostic modalities.
Subject(s)
Contrast Media/administration & dosage , Liver Neoplasms/diagnostic imaging , Urography , Humans , Neoplasm Metastasis , Radiography, Abdominal , Radionuclide Imaging , Tomography, X-RayABSTRACT
Six cases of odontoid fracture were recognized in patients with metastatic carcinoma of the breast. The clinical findings, radiographic diagnosis, and possible neurological sequelae are discussed. While pathologic long bone fractures are often aggressively treated, pathologic odontoid fractures are frequently not recognized despite their prognostic significance. Since patients with osseous metastasis from breast carcinoma may live for many months and undergo general anesthetic procedures that require neck manipulation, its recognition is clinically important.
