Received for publication October 15, 2007.
Revised November 26, 2007.
Accepted for publication November 26, 2007.

POTENT INHIBITION OF HUMAN AP ENDONUCLEASE 1 BY ARYLSTIBONIC ACIDS

Abstract

Human apurinic/apyrimidinic endonuclease (Ape1) plays an important role by processing the >10,000 highly toxic abasic sites generated in the genome of each cell every day. Ape1 has recently emerged as a target for inhibition as its overexpression in tumors has been linked with poor response to both radiation and chemotherapy and lower overall patient survival. Inhibition of Ape1 using siRNA or the expression of a dominant-negative form of the protein have been shown to sensitize cells to DNA-damaging agents, including various chemotherapeutic agents. However, potent small molecule inhibitors of Ape1 remain to be found. To this end, we screened Ape1 against the NCI Diversity Set of small molecules and discovered aromatic nitroso, carboxylate, sulfonamide and arylstibonic acid compounds with micromolar affinities for the protein. A further screen of a 37-compound arylstibonic acid sublibrary identified ligands with IC₅₀ values in the range 4 to 300 nM. The negatively charged stibonic acids act by a partial-mixed mode, and likely serve as DNA phosphate mimics. These compounds provide a useful scaffold for development of chemotherapeutic agents against Ape1.

Key words: Fluorescence techniques, DNA damage and repair