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Publication Abstract from PubMed

Human type II topoisomerase (Top2) isoforms, hTop2alpha and hTop2beta, 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 hTop2alpha and hTop2beta 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-N2beta, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2beta more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2beta are practically irreversible. Crystallographic analyses of hTop2beta complexed with DNA and etoplatin-N2beta 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.

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.,Wang YR, Chen SF, Wu CC, Liao YW, Lin TS, Liu KT, Chen YS, Li TK, Chien TC, Chan NL Nucleic Acids Res. 2017 Oct 13;45(18):10861-10871. doi: 10.1093/nar/gkx742. PMID:28977631^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.