Gold-derived therapeutic compounds for disease application

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PROJECT SUMMARY/ABSTRACT. Gold-derived anticancer compounds are promising therapeutic agents for disease applications, including cancer. Triple negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that lacks effective therapy. Approximately, 66% of all breast cancer deaths are TNBC-related, hence pragmatic treatment options are sorely needed. Our research program seeks to harness the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for new targeted therapeutic regimen to eliminate TNBC. We have developed gold compound libraries with different scaffolds and distinct mode of action in TNBC cells including modulating mitochondrial biogenesis and morphology. The compounds display high potency in the nanomolar range with >30-fold selectivity to cancer cells over normal cells. Comparative profiling using the NCI-60 screen confirmed toxicity of a lead compound, AuPhos against a panel of breast cancer including TNBC. Preliminary maximum tolerated dose studies in BALB/c mice suggest that different classes of gold compounds can be well tolerated in animals. Additionally, AuPhos exerts profound antitumor effect and prevents liver metastasis in the metastatic 4T1 TNBC mouse model. Mechanism of action studies suggest that the gold compounds target different mitochondrial processes including mitochondrial biogenesis or morphology. We hypothesize that synthetic modification of the gold scaffold will enable the development of a suite of gold-based drugs that are targeted to different mitochondrial locales and biological targets to eliminate TNBC. We will test the hypothesis in this project via the following aims: Aim 1) optimize chemically and functionally diverse gold anticancer agents; Aim 2) Delineate the mechanism of gold-based modulation of mitochondrial function; and Aim 3) Determine the therapeutic index of optimized gold compounds in TNBC mouse models. The outcomes of this project will 1) provide novel gold-based compounds with specificity for mitochondrial function to eliminate TNBC; 2) delineate the mechanism of TNBC inhibition by the developed gold-based compounds; and 3) establish in vivo efficacy and pharmacodynamics of gold anticancer agents. Critically, the compounds generated will provide impetus for targeted therapies for TNBC, which is an unmet need.