Miller School of Medicine >> UM Innovation >> Technology Transfer >> For Industry
 
ID# UME-28
MRET-Based Discovery of Allosteric Drug Binding Sites in Flexible Multidomain Protein Kinases for use in Development of Novel Cancer Drugs
Thomas K. Harris
 
Problem
 In many cancers, oncogenic transformation has been found to correlate with increased activation of a number of signal transduction pathways mediated internally by members of the serine-threonine protein (STP) kinase family.  Efforts are being directed towards design of potent and selective inhibitors of well established protein kinase drug targets. Since the overwhelming majority of protein kinase inhibitors bind in or near the ATP binding pocket shared by the catalytic domain of all kinases, very few STP kinase inhibitors have been clinically approved due to their broad specificity and overall high toxicity.
 
Solution
The MRET-based approach for discovery of allosteric drug binding sites in multi-domain protein kinases combines segmental isotopic labeling of the regulatory domain with site directed paramagnetic spin labeling of the kinase domain. It is a unique way of approaching STP kinases in a selective way.  By determination of the overall orientation of the contiguous domains, newly identified clefts and crevices can be targeted for structure and fragment-based drug discovery of compounds that stabilize inactive or autoinhibited conformations of the full length protein kinase.
 
Competitive Advantage
Protein kinases are known to play a critical role in the transformation of cancer cells.  This invention is a unique approach for discovering cancer drugs that inhibit protein kinases.
 
Applications
Several embodiments are envisioned, including a wipe test for suspect wood in residential use, and a dissolution test for suspect mulch used in playgrounds and gardening.  In solid waste handling facilities the invention may be used to test combusted ash, or directly applied to suspect wood.
 
Patent Status
International Patent Appln No. PCT/US2006/022737 entitled “METHOD FOR DESIGNING MODULATORS OF FLEXIBLE MULTI-DOMAIN PROTEIN KINASES” was filed on June 12, 2006.
 
Licensing Opportunity
We are seeking collaborative research and licensing options for the novel identification of drug binding sites and discovery of new cancer drugs.
 
About the Inventors
Dr. Thomas Harris is an Assistant Professor in the Department of Biochemistry and Molecular Biology in the School of Medicine and the Department of Chemistry in the College of Arts and Sciences.  He holds a Ph.D. in biochemistry from the University of Mississippi Medical Center and received postdoctoral training at Johns Hopkins University.
 
Selected References
Harris TK.  Discovering new drug targeting sites on flexible multi-domain protein kinases: combining segmental isotopic and site-directed spin labeling for NMR detection of interfacial clefts.  Methods Mol. Biol. 2005, 316:199-225. Harris TK.  PDK1 and PKB/Akt: ideal targets for development of new strategies to structure based drug design. IUBMB Life. 2003, 55:117 126. Gao X, Yo P, Keith A, Ragan TJ and Harris TK.  Thermodynamically balanced inside out (TBIO) PCR based gene synthesis: a novel method of primer design for high fidelity assembly of longer gene sequences. Nuc. Acids Res. 2003, 31(22), e143.
 
 

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