Protein kinases, as key cellular pathway regulators, are frequently linked to disease and provide opportunities for therapeutic intervention. Due to their prevalence and importance, strict regulation of kinase activity is necessary to control essential cellular processes including the cell cycle, proliferation, differentiation, motility, an cell death or survival. Small molecule kinase inhibitors selected for their ability to target the kinase ATP-binding pocket have achieved clinical utility. However, the high sequence and structural conservation of the pocket found in the more than 500 human protein kinases has created a challenge to developing inhibitors specific for individual kinases. Many limitations in using these small molecule inhibitors derive from their cross-inhibition of other kinases unconnected to the targeted disease process. Part of the mechanism through which protein kinases achieve precise regulation, though, involves integration of many inter- and intramolecular signals via sites that are considerably less well conserved in sequence and function. These non-conserved mechanisms of regulation therefore provide the opportunity for more precise therapeutic targeting, for example, through the development of allosteric inhibitors based on high-affinity and high-specificity ligands. However, it is challenging to identify such allosteric sites in detai. Recently, my sponsor's laboratory identified a previously unknown allosteric network of amino acids that spans the length of the kinase and may thus facilitate integration of allosteric signals into the regulation of protein kinase catalytic domain activity. I propose to experimentally probe the allosteric network and identify ligands that stabilize a predicted allosteric pocket. The findings from this work will deepen our understanding of the fundamental regulatory mechanisms for this important class of drug targets and potentially open the way to the development of more specific therapeutics.
Dysregulated kinase activity underlies many features of cellular pathogenesis, including self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, sustainment of angiogenesis, and tissue invasion and metastasis. The high sequence and structural conservation of the protein kinase catalytic domain creates a challenge for developing specific inhibitors. The goals of my studies are to determine how protein kinases integrate signals from less-well conserved regulatory sites and how we could make use of this integration for therapeutic intervention. The findings from my experiments will provide an important step in the process of developing more specific and thus more useful small molecule therapeutics.
|Maianti, Juan Pablo; McFedries, Amanda; Foda, Zachariah H et al. (2014) Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511:94-8|