The use of metals in medicine has grown impressively in recent years as the result of greatly advanced understanding of the structures of biologically active metal complexes and metal-containing proteins. The goal of this project is to develop a platform that specifically inhibits zinc finger transcription factors (TFs), specifically the Gli family. Gli family TFs represent the final step in the hedgehog (Hh) pathway. The over- activation of this pathway is associated with the growth of a variety of tumors including basal cell carcinoma (BCC) and medulloblastoma. Therefore, inhibitors of these TFs represent potent research tools for biology and have potential use as an entirely new class of therapeutic agents. We are developing cobalt(III)-Schiff base complexes (Co(III)-DNA) that inhibit TFs by a unique mechanism. The complexes are targeted to specific proteins by conjugating decoy oligonucleotides mimicking the native DNA target site of the protein of interest. Subsequent coordination of the cobalt complex to histidines in the zinc finger domain disrupts the structure leading to irreversible inhibition of transcriptional activity. Previous work from our lab has shown that Co(III)-DNA targeted to Snail TFs block EMT in breast cancer cell lines. Preliminary studies in our lab has shown that Co(III)-DNA selectively inhibits Ci (the Drosophila homologue of Gli) in non-mammalian embryo models of development. Here, new Co(III)-DNA conjugates targeted to Gli TFs will be evaluated for their capacity to specifically inhibit Gli transcriptional activity and the Hh pathway in mammalian cell-based reporter assays, and in disease-relevant BCC cell lines. In Aim 1, we will study the interaction of Co(III)-Schiff base and Co(III)-DNA with the Gli DNA binding domain in detail using hydrogen-deuterium exchange coupled with ESI-mass spectrometry. In Aim 2 we will examine the specificity of Co(III)-Gli DNA, comparing targeting to Gli vs. a different transcription factor (Zic) that
|Effective start/end date
|7/15/17 → 4/30/22
- National Institute of General Medical Sciences (5R01GM121518-04)
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