CRT0044876

6960-45-8

206.15

DMSO : 50 mg/mL (242.54 mM; Need ultrasonic)

Cell Cycle/DNA Damage

CRT0044876 is a potent and selective apurinic/apyrimidinic endonuclease 1 (APE1) inhibitor (IC₅₀=ca.3 uM). CRT0044876 inhibits the AP endonuclease, 3?-phosphodiesterase and 3?-phosphatase activities of APE1, and is a specific inhibitor of the exonuclease III family of enzymes to which APE1 belongs. CRT0044876 potentiates the cytotoxicity of several DNA base-targeting compounds^[1]. In Vitro: A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. CRT0044876 has an IC₅₀ for inhibition of APE1 of ?3 uM and not only inhibits AP site cleavage catalyzed by purified APE1, but also cleavage directed by APE1 in a HeLa whole cell extract. CRT0044876 inhibits the 3?-phosphoglycolate diesterase activity of APE1 with an IC₅₀ of ?5 uM^[1].
CRT0044876 inhibits both the exonuclease and AP endonuclease activities of exonuclease III, but shows no inhibitory activity towards endonuclease IV. CRT0044876 has minimal effects on BamHI restriction endonuclease or topoisomerase I even at CRT0044876 concentrations of 100 uM^[1].
At non-toxic concentrations, CRT0044876 potentiates the cytotoxicity of several DNA damaging agents, which generate damage that is repaired in the BER pathway, including some currently-used anticancer drugs. The combination of MMS and CRT0044876 leads to a synergistic increase in the level of AP sites. Consistent with CRT0044876 being a specific BER inhibitor, a strong potentiation of hmdUrd cytotoxicity is seen in CRT0044876-treated cells (HT1080 cells)^[1].