Background:

CRT0044876 is a potent and selective inhibitor of APE1 with IC50 value of 3.06 μM [1].

Apurinic/apyrimidinic endonuclease-1 (APE1) is a member of the highly conserved exonuclease

III family of AP endonucleases and plays an important role in DNA repair. APE1 exhibits 3’-phosphodiesterase activity and weak 3’-phosphatase activity, 3’-5’-exonuclease activity and RNaseH activity [1].

CRT0044876 is a potent and selective APE1 inhibitor. In HeLa whole cell extract, CRT0044876 inhibited apurinic/apyrimidinic (AP) site cleavage catalyzed by APE1. CRT0044876 inhibited both the AP endonuclease and exonuclease activities of exonuclease III, the bacterial homologue of APE1. CRT0044876 inhibited the 3’-phosphoglycolate diesterase activity of APE1 with IC50 value of 5 μM and also inhibited 3’-phosphatase activity through binding to DNA repair active site of APE1. In HT1080 fibrosarcoma cells, CRT0044876 significantly increased AP site accumulation and was non-toxic at concentrations up to 400 μM. Also, CRT0044876 potentiated the cytotoxicity induced by alkylating agent MMS, temozolomide, hydrogen peroxide and hmdUrd through specific inhibition of the base excision repair (BER) pathway [1].

Reference:
[1].  Madhusudan S, Smart F, Shrimpton P, et al. Isolation of a small molecule inhibitor of DNA base excision repair. Nucleic Acids Res, 2005, 33(15): 4711-4724.