<br/>Transcription factors (TFs) are key mediators of cancer signaling and disease progression. Snail family TFs are involved in the onset of metastasis, a process responsible for the vast majority of cancer-associated fatalities. Gli family TFs represent the final step in the hedgehog (Hh) pathway. Overactivation of the Hh pathway is associated with growth and proliferation of a variety of tumors including basal cell carcinoma, medulloblastoma, and pancreatic cancer. Therefore, inhibitors of these TFs are powerful research tools for cancer biology and have potential use as the chemotherapeutic 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 through decoy oligonucleotides mimicking the native binding partner of the protein of interest. Coordination of the Co(III) complex to histidines in the protein disrupts structure, leading to irreversible inhibition of transcriptional activity.<br/>We have demonstrated selective inhibition of Snail and Gli TFs by Co(III)-DNA in non-mammalian embryo models of development. Snail-targeted Co(III)-DNA block the known functions of the TF in the formation and migration of neural crest cells in Xenopus embryos, while the Snail-independent pathways remain unaffected. In a similar fashion, Gli-targeted Co(III)-DNA inhibited Hh-associated denticle belt formation in Drosophila embryos selectively at the site where agent was injected. The mechanism of TF inhibition by the Co(III)-DNA was investigated spectroscopically with model peptides of zinc finger motifs (the structures responsible for the DNA-binding activity of Snail and Gli TFs). The mechanism we describe focuses on Co(III) Schiff base complexes that inhibit protein activity through selective histidine coordination in the zinc fingers via dissociative ligand exchange. Histidine-coordination disrupts the ββα structural motif required for gene regulation. We are investigating this versatile Co(III)-DNA platform in mammalian systems to inhibit Snail- and Gli-associated pathways in cancer.

Cobalt Schiff base complexes as targeted inhibitors of transcription factors

249th National Meeting (2015)

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