Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2

Christophe Marchand, Monica Abdelmalak, Jayakanth Kankanala, Shar Yin Huang, Evgeny Kiselev, Katherine Fesen, Kayo Kurahashi, Hiroyuki Sasanuma, Shunichi Takeda, Hideki Aihara, Zhengqiang Wang, Yves Pommier

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1925-1933
Number of pages9
JournalACS Chemical Biology
Volume11
Issue number7
DOIs
StatePublished - Jul 15 2016

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