Exploration of substitutionally inert octahedral rhodium(III) complexes as direct inhibitors of signal transducer and activator of transcription 3.

Signal transducer and activator of transcription (STAT) proteins are a family of transcription factors that mediate gene expression in response to cytokines and growth factors. STAT3 regulates a variety of genes involved in cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity. Dysregulated STAT3 activity has been implicated in the development of a variety of solid and hematological tumors, including leukemia, lymphomas and skin cancer. Additionally, elevated STAT3 levels have been associated with poor prognosis of certain cancers. The central role of aberrant STAT3 signaling in tumorigenesis has rendered STAT3 as an attractive target in anti-cancer therapy. However, no compound discovered as a STAT3 inhibitor a priori has yet been approved for clinical use.

Substitutionally-inert octahedral rhodium(III) complexes have recently been reported by our group to represent promising scaffolds for the development of direct STAT3 dimerisation inhibitors with potent in vitro and in vivo activities. The objective of this proposal is to investigate a larger range (around 100) of substitutionally-inert rhodium(III) complexes as direct inhibitors of the STAT3 protein-protein interaction. Metal complexes possess a unique molecular architecture that can allow them to effectively explore the chemical space of protein-protein interfaces that are inaccessible to purely organic molecules. Furthermore, the facile and modular nature of metal complex synthesis allows the interactions between the metal complexes and the SH2 domain of STAT3 to be fine-tuned simply by modification of the auxiliary ligands rather than through extensive synthetic procedures. Finally, kinetically- inert metal complexes are less likely to induce adverse side-effects that can be observed with metal-based drugs that form covalent bonds with cellular protein or DNA.

Based on the results of our preliminary communication (Angew. Chem. Int. Ed., 2014, 53, 9178) we will rationally design and synthesize new series of rhodium(III) complexes using a computer-assisted, bioassay-guided parallel methodology. To achieve superior affinity and selectivity for STAT3, we will investigate the addition of bulkier aromatic co-ligands to the metal complexes to allow them to recognize the hydrophobic sub-pockets of the SH2 domain of STAT3. The novel complexes will be extensively characterized and tested using biological assays to determine their potencies against STAT3 activity in vitro and in cellulo. The role of STAT3 as a target in metal-induced cytotoxicity will also be validated using STAT3 knockdown cells. Furthermore, computer-aided docking analysis and experimental structure- activity relationships will be harnessed to develop analogues with higher efficacy against STAT3 activity with each successive generation. The most potent complexes will be tested in vivo in a mouse xenograft model of melanoma. We anticipate that the rhodium(III) complexes could eventually be developed as highly potent and selective lead candidates against the STAT3 protein-protein interaction. The most active compounds developed in this study could potentially be utilised as anti-tumor agents for the treatment of skin or other cancers. Given that protein-protein interactions are typically considered to be difficult to target due to their large and featureless interfaces, as well as the emerging use of substitutionally- inert metal complexes as molecularly-targeted therapeutics, the results of this project will be of high interest to the scientific community and may potentially represent a significant breakthrough in the treatment of proliferative diseases.