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Small Molecule Inhibitors of the Human Apurinic/apyrimidinic Endonuclease 1 (APE1).


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2010 Oct 29 [updated 2013 Feb 28].

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NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland.
National Institute on Aging, National Institutes of Health, Bethesda, Maryland.


Probe compound, ML199, and related inhibitors of Apurinic/apyrimidinic (AP) endonuclease (APE1) are reported herein. APE1 is a key component of the base excision repair (BER) pathway that is responsible for repair of DNA damage caused by many anti-cancer agents such as bleomycin and temozolomide. As a result, inhibition of APE1 has been postulated as a viable strategy for sensitizing tumor cells to chemotherapy. ML199 and its related analogs belong to a drug-like series that was identified and optimized through a focused medicinal chemistry effort to afford compounds which display competitive inhibition of APE1 activity in the low micromolar potency range. On target effect of the ML199 was demonstrated through a concentration depended inhibition of AP site incision activity in whole cell HeLa extracts. Moreover, ML199 potentiated the cytotoxicity of the DNA alkylating agent methylmethane sulfonate (MMS) at non-cytotoxic doses of the probe compound. The probe and its general class of compounds have shown to have good kinetic solubility, Caco-2 permeability, metabolic stability and other favorable physicochemical properties, thus making ML199 an ideal starting point for further pre-clinical development of anti-cancer agents.

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