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

ABSTRACT: Human type II topoisomerase (Top2) isoforms, hTop2? and hTop2?, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2? and hTop2? revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2?, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2? more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2? are practically irreversible. Crystallographic analyses of hTop2? complexed with DNA and etoplatin-N2? demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

SUBMITTER: Wang YR 

PROVIDER: S-EPMC5737487 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature