Functional Disruption of Gli1‐DNA Recognition via a Cobalt(III) Complex

• Published in: ChemMedChem 2022-04, Vol.17 (8), p.e202200025-n/a
• Main Authors: Brue, Christopher R., Dukes, Meghan W., Masotti, Meghan, Holmgren, Robert, Meade, Thomas J.
• Format: Article
• Language: English
• Subjects: Basal cell carcinoma; Binding sites; Cancer; Cobalt; Cobalt - chemistry; Cobalt - pharmacology; Computer applications; Conserved sequence; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA recognition; Humans; Inhibitors; Medulloblastoma; molecular dynamics; Nucleotide sequence; Recognition; Transcription factors; Transcription Factors - metabolism; Zinc; Zinc Finger Protein GLI1; Zinc finger proteins; Zinc Fingers
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200025

The aberrant activation of the Gli family of zinc finger transcription factors (ZFTFs) is associated with several types of human cancer, including medulloblastoma and basal cell carcinoma. We have reported the use of cobalt(III) Schiff‐base complexes (Co(III)‐sb) as potent inhibitors of ZFTFs in vivo. These complexes inhibit transcription by displacing the zinc finger domain‘s structural Zn(II) ion, destabilizing the alpha helix necessary for DNA recognition. Here, we describe the use of Co(III)‐sb complexes for the selective inhibition of Gli1. Spectroscopic and computational studies of the Gli1 DNA binding domain found that Co(III)‐sb displaced Zn(II) through direct coordination with the His residues of the Cys2His2 Zn(II) binding site. As a result, there is a dose‐dependent degradation of the alpha‐helix content in the DNA binding domain of Gli1 and corresponding inhibition of consensus sequence recognition. We conclude that this strategy is well suited for the development of new and potent inhibitors of Gli1. Co(III) Schiff‐base complexes displace native Zn(II) ions from zinc finger transcription factors overexpressed in many types of cancer. As a result, the helical secondary structure necessary for consensus DNA sequence recognition is structurally compromised. We used a Co(III)‐sb to inhibit the Gli1 zinc finger transcription factor, which is known to cause aberrant activation of the Hedgehog pathway in basal carcinoma, medulloblastoma, and pancreatic adenocarcinoma.