Transition metals have found broad applicability for human health, most often as drugs and diagnostic imaging agents.  In contrast, one of the most common commercial applications of small transition metals, catalysis, has been largely unexplored as a tool for the study and treatment of disease.  This void in the field is attributable in part to long-held dogmas about the toxicity and instability of transition metal catalysts in biological environments.  Only now, on the heels of important advances in biocompatible catalyst development by our lab and others, is small molecule transition metal catalysis inside living cells a possibility.  We herein demonstrate a broadly applicable strategy for transition metal induced control of enzyme inhibition by catalytic uncaging of prodrugs.  We also discuss the advantages of this method, specifically �On Demand� temporal control of prodrug uncaging, over current technologies.  This technology will be demonstrated to be useful for the inhibition of kinases, which are key targets for the study and treatment of diseases ranging from cancer to Alzheimer's disease and diabetes.  We also describe a method for the transition metal catalyzed intracellular synthesis of molecular libraries to streamline the drug discovery process by combining screens for cellular drug activity and toxicity into a single, high-throughput cellular assay. This technology is being developed using a protein tyrosine phosphatase model system, which is a highly important but underdeveloped class of enzyme for drug discovery.

Transition metal catalysts as novel tools for intracellular enzyme inhibition

248th National Meeting (2014)

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