The activation of survival pathways is a major feature of tumor cells which contributes to the limited efficacy of antitumor treatment based on conventional cytotoxic drugs and on molecularly targeted agents. The deregulation of oncogenic signaling pathways providing survival advantages to tumor cells is mediated by several cellular networks which include different protein kinases. The human genome comprises more than 500 protein kinases including serine/threonine, tyrosine and dual specificity kinases. Because of the important physiological and pathological role of kinases, the human kinome represents one of the most important drug discovery opportunities in different therapeutic areas, including oncology. Protein kinases comprise a large family of enzymes that catalyse the transfer of the terminal phosphate group from ATP (adenosine triphosphate) to protein substrates, specifically to the hydroxyl group of serine or threonine (Ser/Thr kinases) or tyrosine (Tyr kinases). Since protein kinases represent key players in many crucial cellular processes like proliferation, differentiation, and apoptosis, the discovery of small molecule kinase inhibitors has attracted growing interest for novel drug research and development as well as the identification of experimental tools for the understanding of the biological roles of this class of proteins. Among the kinases implicated in aberrant tumor cell signaling, the serine/threonine protein kinase B (PKB), also known as Akt, plays a key role as a component of the PI3K-Akt-mTOR axis. The generation of novel Akt inhibitors not directed to the ATP binding pocket, but targeting the PH domain may confer some degree of selectivity towards the target as compared to other kinase inhibitors. Therefore, the specific aims of the present proposal are : to design, synthesize and test new PH domain targeted Akt inhibitors based on D-glucose and sulfoglycolipids. Combined high-quality docking simulations and high-resolution NMR epitope mapping experiments will be employed in this context. To improve the understanding of the biological roles of Akt in tumor cell biology with special emphasis on chemoresistance and invasiveness, using the prepared compounds. To explore the capability of the compounds to increase sensitivity of tumor cells to conventional cytotoxic agents as well as to target-specific agents. To define the antitumor activity of selected compounds in
in vivo
models.