ABSTRACT
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Animals , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Computer Simulation , Humans , Mice , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyrimidinones/therapeutic use , Rats , Structure-Activity Relationship , Transplantation, Heterologous , Up-RegulationABSTRACT
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Pyridines/chemical synthesis , Pyrrolidines/chemical synthesis , Adenosine Deaminase/chemistry , Administration, Oral , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dogs , Female , Glucose Intolerance/drug therapy , Glycoproteins/chemistry , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Macaca fascicularis , Models, Molecular , Molecular Structure , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of potent steroidal glucocorticoid receptor antagonists has been discovered. After conjugation to cholic acid, the compounds retained an affinity for GR in vitro and had modest in vivo efficacy.
