Gold-derived therapeutic compounds for disease application

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.

Grant Number: 5R01CA258421-05
NIH Institute/Center: NIH
Principal Investigator: Samuel Awuah