Development of Membrane-Protein Interaction Modulators as Allosteric Drug Candidates

The serine/threonine kinase Akt, also known as protein kinase B (PKB), plays a critical role in regulating diverse cellular functions, including cell survival, proliferation, migration and differentiation. Dysregulation of Akt contributes to tumorigenesis, tumor metastasis, and resistance to chemotherapy or radiotherapy. Akt has three isoforms (Akt1, Akt2 and Akt3) that have both redundant and distinct roles in cell regulation. Akt isoforms share a high degree of sequence homology in their catalytic domains and thus orthosteric Akt inhibitors targeting the ATP-binding site show low isoform specificity and clinical efficacy. To overcome this problem, we developed new isoform-specific allosteric Akt inhibitors targeting the membrane binding surfaces of Akt isoforms. These inhibitors showed high potency and specificity in both in vitro and cell-based assays. We also developed a novel inhibitor targeting the membrane binding site of the most frequently found oncogenic mutant (E17K) of Akt1. This inhibitor specifically inhibited the E17K mutant of Akt1 without the binding to Akt1 wild type and other Akt isoforms in both in vitro and cell-based assays.