ABSTRACT
A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity RelationshipABSTRACT
We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Spiro Compounds/chemistry , Sulfonamides/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Cyclic AMP-Dependent Protein Kinases/metabolism , Drug Evaluation, Preclinical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/chemistry , Pyrroles/chemistry , Adaptor Proteins, Signal Transducing , Animals , Binding Sites , Cell Line , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Mice , Phosphoproteins/deficiency , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A cytoplasmic activity in mature oocytes responsible for second meiotic metaphase arrest was identified over 30 years ago in amphibian oocytes. In Xenopus oocytes cytostatic factor (CSF) activity is initiated by the progesterone-dependent synthesis of Mos, a MAPK kinase kinase that activates the MAPK pathway. CSF arrest is mediated by a sole MAPK target, the protein kinase p90(Rsk). Rsk phosphorylates and activates the Bub1 protein kinase, which may cause metaphase arrest due to inhibition of the anaphase-promoting complex (APC) by a conserved mechanism defined genetically in yeast and mammalian cells. CSF arrest in vertebrate oocytes by p90(Rsk) provides a link between the MAPK pathway and the spindle assembly checkpoint in the cell cycle.
