Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1

Apurinic/apyrimidinic
endonuclease 1 (APE1) is an essential base
excision repair enzyme that is upregulated in a number of cancers,
contributes to resistance of tumors treated with DNA-alkylating or
-oxidizing agents, and has recently been identified as an important
therapeutic target. In this work, we identified hot spots for binding
of small organic molecules experimentally in high resolution crystal
structures of APE1 and computationally through the use of FTMAP analysis
(http://ftmap.bu.edu/). Guided
by these hot spots, a library of drug-like macrocycles was docked
and then screened for inhibition of APE1 endonuclease activity. In
an iterative process, hot-spot-guided docking, characterization of
inhibition of APE1 endonuclease, and cytotoxicity of cancer cells
were used to design next generation macrocycles. To assess target
selectivity in cells, selected macrocycles were analyzed for modulation
of DNA damage. Taken together, our studies suggest that macrocycles
represent a promising class of compounds for inhibition of APE1 in
cancer cells.