Gold-derived Therapeutic Compounds for Disease Application

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Mitochondrial metabolism is crucial for physiological processes spanning cell signaling & growth, gene expression, and immune response. At the same time, mitochondrial dysfunction contributes to neurodegenerative, cardiovascular, ageing, and cancer progression. Current strategies with metal agents or organic small-molecule probes that target mitochondria have either poor target potency (e.g metformin), unclear mechanisms, or their toxicity (e.g rotenone) precludes in vivo application. Thus, potent, selective, and in vivo tolerable chemical reagents are urgently needed. The major objective of our research program is to develop novel gold-based compounds as agents that selectively alter and probe distinct mitochondrial functions. The significance of this proposal is the development of new chemical modulators for the often- intractable mitochondrial pathways including OXPHOS. Our research program has made significant contributions already by developing biologically active gold compounds that either inhibit OXPHOS (AuDTC), increase OXPHOS and mitochondrial biogenesis, or modify mitochondrial structure in vitro and in vivo. We have made foundational discoveries regarding mitochondrial metabolism in triple negative breast cancer (TNBC), defined how complex I impact cellular processes, developed cutting-edge tools to determine the underlying cellular mechanisms, and established therapeutic platforms to inhibit mitochondrial complex I. We hypothesize that mitochondrial metabolism are a driving force for disease progression in TNBC. Defining the mechanisms of mitochondrial metabolism in TNBC provides insights into the dependence of aggressive tumors on mitochondria for growth. This supplement will allow Mr. Omar Bojang to further hone his skills in translational therapeutics. His results will assist in determining the role of mitochondrial complex I inhibition in TNBC. He will look at modifications of lead AuDTC compound in perturbing the mitochondrial mechanisms at the molecular level and establish novel therapeutic modalities at the organismal level.