BACKGROUND:  Kinases, such as protein kinase B/Akt, frequently show gain of function in cancer. Activated Akt has diverse functions that affect a broad spectrum of cellular activities related to growth, survival, and differentiation. The gain of function in Akt affects the regulation of cell growth and of apoptosis. Therefore, increased Akt activity in cancer cells results in resistance to drug-induced apoptosis and enhanced cell replication. Current available anticancer treatments are small molecule kinase inhibitors that function by blocking the ATP pockets of the enzymes. However, since the ATP pockets of different kinases can be structurally similar, inhibitors suffer from a lack of specificity and produce unacceptable side effects. The development of Akt inhibitors with high selectivity or high specificity is therefore highly desired.

INNOVATION:  Researchers at UCLA have generated novel bivalent ligand kinase Akt inhibitors ("biligands"), which simultaneously access the ATP and substrate pockets, through a combinatorial click chemistry approach. Biligand libraries were prepared from two classes of building block libraries - one that binds to the ATP pocket, and a second building block library that presumably accesses the substrate pocket. The biligand libraries were screened for Akt inhibition, yielding several low nanomolar inhibitors that are specific for Akt1.

POTENTIAL APPLICATIONS 

• Use in a molecular diagnostic setting for developing in vivo imaging probes or in vitro diagnostic probes for the cancer-related kinase Akt
• Develop therapeutic drugs that act against Akt-dependent cancers and other related malignancies, such as diabetes

ADVANTAGES

• Displays several orders of magnitude higher affinities for the target protein than other small molecule inhibitors
• Unlikely for biligand inhibitors to interact with other kinases
• Distinction between Akt isoforms 1, 2 and 3
• Higher specificity, selectivity and potency

Reference: UCLA Case No. 2007-189