AGC Kinases: From Molecular Mechanism of Regulation to Allosteric Drug Development

BIONDI RM

Berlin

Congreso; 2nd Kinase Inhibitors Design and Screening; 2016

GTC Global Technology Community

The group of AGC kinases comprise more than 60 members in humans, including Akt/PKB, PKCs, PDK1, GRKs, S6Ks, etc. The catalytic domain of AGC kinases possess a regulatory site (termed PIF-pocket), that is a key ON-OFF switch, mediating in different kinases, their activation by phosphorylation, inhibition by N-terminal domains, mediating regulated docking interaction with substrates, etc. Small molecules directed to the PIF-pocket can allosterically activate or allosterically inhibit protein kinases, or can be substrate selective inhibitors in cells. I will describe our investigations into the modulation of the allosteric process by the small compounds in the model kinase PDK1 and discuss some principles that can be exploited for allosteric drug developments to protein kinases.