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

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.