期刊
ACS CHEMICAL BIOLOGY
卷 11, 期 7, 页码 1925-1933出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.5b01047
关键词
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资金
- Faculty Research Development Grant of the Academic Health Center, University of Minnesota
- JSPS Core-to-Core Program A. Advanced Research Networks
- Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute [Z01 BC 006161-17LMP]
- Grants-in-Aid for Scientific Research [16H02953, 16H06306] Funding Source: KAKEN
Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegans TDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance. Among them, human residues L313 and T296 confer high resistance when mutated to their mouse counterparts. Moreover, deazaflavin derivatives show potent synergy in combination with the topoisomerase II inhibitor etoposide in human prostate cancer DU145 cells and TDP2-dependent synergy in TK6 human lymphoblast and avian DT40 cells. Deazaflavin derivatives represent the first suitable platform for the development of potent and selective TDP2 inhibitors.
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