DRUG DISCOVERY OF PKB INHIBITORS AS ANTI-TUMOR AGENTS
This proposal focuses on the discovery and investigation of novel compounds as potential drugs for the treatment of cancer through the inhibition of Protein Kinase B (PKB), also known as Akt. The project will center on the discovery of PKB inhibitors through structure-based, rational drug design aided by a molecular modeling tool known as Molecular Operating Environment (MOE). An initial set of compounds as potential PKB inhibitors will be synthesized using a novel synthetic and catalytic method developed in our laboratory involving the use of gallium. The design of this initial set of compounds designed from an original lead of compounds belonging to the quinoxalines and pyridinopyridines chemical series. These compounds were discovered in the investigator’s laboratory at ImClone Systems, Inc. while he served as the Principal Investigator of their drug discovery program. The final goal will be to develop an irreversible and selective PKB/Akt inhibitor from the current quinoxaline lead compound. These quinoxaline compounds with an irreversible, binding war-head were designed from a second generation of quinoxaline and pyridinopyridine chemical series synthesized in the laboratory of Dr Kawakami at Chaminade University of Honolulu. The design was based on ligand to protein docking interaction for the appropriate placement of these war-heads. All compounds synthesized and fully characterized from this research plan will also be tested enzymatically at PKBa in our laboratory utilizing a combination of an Enzyme-Linked Immunosorbent assay (ELISA) and Homogeneous Time Resolved Fluorescence (HTRF) assays. The further testing of potent enzymatically active inhibitors at PKBa (IC50 < 500 nM) will be evaluated in a HTRF cell-based assay.