The PKB/Akt pathway has been identified as an important regulator of cell survival signaling.The Akt protein family members (Akt 1-3) are known to be involved in a wide variety of biological processes including cell proliferation,differentiation, apoptosis, and tumorigenesis.These enzymes are members of the serine/threonine-specific protein kinase family.There has been significant pharmaceutical interest in the development of Akt inhibitors, most extensively around the development of ATP competitive inhibitors, and a number of such compounds are reported to be in preclinical or early clinical studies.More recently, Akt inhibitors which do not bind at the ATP site of the kinase have also been reported.Despite the significant interest, there are still relatively few Akt inhibitors in clinical development.Almac Discovery has identified several chemical series of novel, allosteric Akt inhibitors which can be tuned to provide differing selectivity profiles for the three Akt isoforms.Compounds with a range of selective profiles exhibit good single agent efficacy in a panel of cell-lines, as show synergy when combined with radiation or other therapeutic agents,including modulators of key parallel signaling pathways.Lead compounds exhibit time and dose dependent knockdown of pathway biomarkers after oral dosing in rodent xenograft models.The profiles of representative examples will be presented.