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

Ying Ren Wang, Shin Fu Chen, Chyuan Chuan Wu, Yi Wen Liao, Te Sheng Lin, Ko Ting Liu, Yi Song Chen, Tsai Kun Li, Tun Cheng Chien, Nei Li Chan

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Abstract

Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, 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 hTop2α and hTop2β revealed the presence of methionine residues in the drugbinding 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-N2β, by replacing the methioninejuxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β 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 isoformspecific targeting of human Top2s.

Original languageEnglish
Pages (from-to)10861-10871
Number of pages11
JournalNucleic Acids Research
Volume45
Issue number18
DOIs
Publication statusPublished - 2017 Oct 13

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ASJC Scopus subject areas

  • Genetics

Cite this

Wang, Y. R., Chen, S. F., Wu, C. C., Liao, Y. W., Lin, T. S., Liu, K. T., Chen, Y. S., Li, T. K., Chien, T. C., & Chan, N. L. (2017). Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry. Nucleic Acids Research, 45(18), 10861-10871. https://doi.org/10.1093/nar/gkx742