Research SummaryTargeting Kinase Protein-Protein Interactions as Cancer Therapy
Kinases are molecular switches which toggle between several catalytically active and inactive conformations for controlled cell-signaling. Although the primarily role of kinases is phosphoryl transfer (canonical function), they also serve as scaffolds to relay allosteric signals (non-canonical function). Oncogenic mutations in kinases disrupt cell-signaling through aberrant activation of kinase resulting in tumor growth. A growing body of evidence associates the aberrant kinase activation in oncogenic mutations with allostery and dynamics. While these mutations have been discovered, their activation mechanisms haven’t yet been deciphered. Preliminary studies with our initial study systems protein kinase A and Aurora kinase, suggest that mutations shift the equilibrium towards the active conformation by modulating the free-energy landscape of kinase and thus hamper its auto-inhibitory function. This leads to rewiring of the protein-protein interaction (PPI) networks. Hitherto the conserved nature of the kinome has rendered most kinase inhibitors targeting the conventional binding-sites less effective. Modulating PPIs is thus a feasible detour to beget specificity and curb cancer. Our goal is to define these entropy driven activation mechanisms, decode the modulations in PPI networks and develop targeted therapies for cancer. We use an interdisciplinary approach integrating computations and experiments to investigate the fundamental differences in molecular assemblies and PPIs of oncogenic kinase mutants. Use the insights thus obtained to develop new methods for the design of target specific kinase drugs.