Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC 50 < 50 µM), with 17z showing excellent cell permeability and no cytotoxicity.
Bibliographical noteFunding Information:
This research was supported by the Academic Health Center Faculty Research Development Grant Program (FRD #14.23), University of Minnesota , and partially by the Center for Drug Design, University of Minnesota, and NIH grant GM118047 to HA. We acknowledge Professor Bert Semler at University of California, Irvine and Professor Haitao Guo at Indiana University School of Medicine, for providing HeLa and HepG2 cells, respectively. We also acknowledge Victor G. Young, Jr. and the X-ray Crystallographic Laboratory for the X-ray crystallography studies. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (#1224900) and the University of Minnesota.
- Tyrosyl-DNA phosphodiesterase 2 (TDP2)
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.