Dysregulation of protein kinase activity has been implicated in a number of diseases, including cancer, diabetes and chronic inflammation. Therefore, protein kinases have emerged as one of the most important drug targets in modern drug discovery. These efforts have resulted in the development of a vast array of small molecule inhibitors that interact with the ATP-binding sites of protein kinases and are able to block their catalytic activities. Interestingly, many of these pharmacological agents exploit the conformational flexibility of the ATP-binding sites of protein kinases by binding to different actie site conformations. For example, the drugs Gleevec (imatinib) and Nexavar (sorafenib) bind to an ATP-binding site conformation of their kinase targets that involves displacement of a catalytically important structural element called the DFG motif. While it has been speculated that certain modes of kinase inhibition lead to more desirable clinical outcomes, there have not been any systematic comparisons at the biochemical and/or cellular level. Our hypothesis is that ATP-competitive inhibitors that stabilize different ATP-binding site conformations of multi-domain protein kinases will have divergent effects on domains and interactions outside of the active site. This leads to the exciting possibility that it may be possible to obtain different phenotypic responses through the inhibition of the same kinase active site by varying the mode of ATP-binding site occupancy. To test this hypothesis, we propose to study how different modes of inhibition affect the SRC family of kinases (SFKs), which are well-characterized, multi- domain tyrosine kinases. SFKs play diverse roles in multiple signaling processes and are important therapeutic targets. Furthermore, it has been demonstrated that beyond their catalytic activities, SFKs also have a number of non-catalytic scaffolding functions that are dependent on their regulatory domains.
This project is focused on characterizing how stabilizing the active sites of SRC-family kinases in specific conformations affect their biochemical and cellular properties. SRC-family kinases are potential therapeutic targets for a number of diseases including cancer and chronic inflammation. These multi-domain enzymes play diverse catalytic and non-catalytic roles in the cell. Exploring how specific active site conformations affect the signaling properties of SRC-family kinases will inform the development of new therapeutics for cancer and inflammation.
|Crowther, Gregory J; Hillesland, Heidi K; Keyloun, Katelyn R et al. (2016) Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. PLoS One 11:e0149996|
|Huang, Wenlin; Hulverson, Matthew A; Zhang, Zhongsheng et al. (2016) 5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents. Bioorg Med Chem Lett 26:5487-5491|
|Feldman, Hannah C; Tong, Michael; Wang, Likun et al. (2016) Structural and Functional Analysis of the Allosteric Inhibition of IRE1Î± with ATP-Competitive Ligands. ACS Chem Biol 11:2195-205|
|Gower, Carrie M; Thomas, Jason R; Harrington, Edmund et al. (2016) Conversion of a Single Polypharmacological Agent into Selective Bivalent Inhibitors of Intracellular Kinase Activity. ACS Chem Biol 11:121-31|
|Vidadala, Rama Subba Rao; Rivas, Kasey L; Ojo, Kayode K et al. (2016) Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis. J Med Chem 59:6531-46|
|Ojo, Kayode K; Dangoudoubiyam, Sriveny; Verma, Shiv K et al. (2016) Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy. Int J Parasitol 46:871-880|
|Pedroni, Monica J; Vidadala, Rama Subba Rao; Choi, Ryan et al. (2016) Bumped kinase inhibitor prohibits egression in Babesia bovis. Vet Parasitol 215:22-8|
|Doggett, J Stone; Ojo, Kayode K; Fan, Erkang et al. (2014) Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection. Antimicrob Agents Chemother 58:3547-9|
|Gower, Carrie M; Chang, Matthew E K; Maly, Dustin J (2014) Bivalent inhibitors of protein kinases. Crit Rev Biochem Mol Biol 49:102-15|
|Vidadala, Rama Subba Rao; Ojo, Kayode K; Johnson, Steven M et al. (2014) Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes. Eur J Med Chem 74:562-73|
Showing the most recent 10 out of 42 publications