Pharmacologic Dissection of the Role of Individual Kinases in Signal Transduction: from Basic Biology to Host-Pathogen Interactions
- Author(s): Rutaganira, Florentine Uwamahoro
- Advisor(s): Shokat, Kevan M
- et al.
As key modulators of cellular processes, kinases are promising disease targets and inhibition of kinases with small molecules has now become an effective means of treating severe diseases. Although kinases play a large role in cellular signaling and aberrant kinase activity can have profound effects on cellular state, many kinases lack pharmacological tools that are potent and specific enough to accurately assess their function. Even fewer kinases possess pharmacologic tools with desirable pharmacokinetic characteristics that are required to assess clinical utility in animal models. Among these kinases are human phosphoinositide kinases, which have been implicated as novel targets for asthma and pan viral replication, as well as parasitic calcium-dependent protein kinases (CDPK) that can serve as novel targets for parasitic diseases. Through multi-lab collaborations, I have designed, synthesized, optimized, and biochemically evaluated ATP-competitive small molecule inhibitors for human type III phosphatidylinositol 4-kinases (PI4KIII) and type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) kinases as well as Toxoplasma gondii CDPK1. We have achieved potent and selective pharmacological tools for these kinases and inhibitors to PI4KIIIβ and TgCDPK1 have been optimized for desirable pharmacokinetic characteristics and serve as clinical leads for pan antivirals and toxoplasmosis respectively.