Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Human type II topoisomerase (hTop2) isoforms, hTop2α and hTop2β, are key targets for anticancer drugs.
• Current drugs stabilize enzyme-mediated DNA breaks, but their efficacy varies.
• Methionine residues in the hTop2 drug-binding pocket present an opportunity for enhanced drug interaction.

Purpose of the Study:

• To develop a novel anticancer agent with improved Top2 inhibition and DNA break stabilization.
• To investigate the potential of platinum coordination chemistry for enhancing Top2-drug interactions.
• To explore isoform-specific targeting of hTop2.

Main Methods:

• Synthesis of an organoplatinum compound, etoplatin-N2β, by incorporating a platinum(II) moiety into etoposide.
• Inhibition assays to compare etoplatin-N2β and etoposide against hTop2α and hTop2β.
• Crystallographic analysis of hTop2β complexed with DNA and etoplatin-N2β.

Main Results:

• Etoplatin-N2β demonstrated more potent inhibition of both hTop2 isoforms compared to etoposide.
• DNA breaks induced by etoplatin-N2β were practically irreversible, unlike those from etoposide.
• Crystallography revealed coordinate bond formation between platinum and a methionine residue in hTop2β, stabilizing the DNA break.

Conclusions:

• Platinum coordination with methionine offers a strategy for creating potent Top2 inhibitors with irreversible DNA breaks.
• Etoplatin-N2β represents a promising lead compound for developing novel anticancer therapeutics.
• This approach may enable the development of Top2 isoform-specific drugs.