TY - JOUR
T1 - Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2
AU - Marchand, Christophe
AU - Abdelmalak, Monica
AU - Kankanala, Jayakanth
AU - Huang, Shar Yin
AU - Kiselev, Evgeny
AU - Fesen, Katherine
AU - Kurahashi, Kayo
AU - Sasanuma, Hiroyuki
AU - Takeda, Shunichi
AU - Aihara, Hideki
AU - Wang, Zhengqiang
AU - Pommier, Yves
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - 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.
AB - 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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U2 - 10.1021/acschembio.5b01047
DO - 10.1021/acschembio.5b01047
M3 - Article
C2 - 27128689
AN - SCOPUS:84978524619
SN - 1554-8929
VL - 11
SP - 1925
EP - 1933
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 7
ER -