Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2)

Jayakanth Kankanala, Christophe Marchand, Monica Abdelmalak, Hideki Aihara, Yves Pommier, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds. Further structure-activity relationship (SAR) studies identified numerous analogues inhibiting TDP2 in low micromolar range without appreciable inhibition against the homologous TDP1 at the highest testing concentration (111 μM). The best compound 64 inhibited recombinant TDP2 with an IC50 of 1.9 μM. The discovery of this chemotype may provide a platform toward understanding TDP2 as a drug target.

Original languageEnglish (US)
Pages (from-to)2734-2746
Number of pages13
JournalJournal of medicinal chemistry
Volume59
Issue number6
DOIs
StatePublished - Mar 24 2016

Bibliographical note

Funding Information:
This research was supported by the Faculty Research Development Grant (to H.A. and Z.W.) of the Academic Health Center, University of Minnesota, and in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute (Z01 BC 006161-17), and the Minnesota Super computing Institute (MSI) for computational resources involving modeling.

Publisher Copyright:
© 2016 American Chemical Society.

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