Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1)

• Published in: Bioorganic & medicinal chemistry 2017-05, Vol.25 (9), p.2531-2544
• Main Authors: Laev, Sergey S., Salakhutdinov, Nariman F., Lavrik, Olga I.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apurinic/apyrimidinic (AP) site; Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1); Base excision repair (BER); Cell Line, Tumor; DNA repair; DNA Repair - drug effects; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - chemistry; E3330; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitors; Lucanthone; Methoxyamine; Neoplasms - drug therapy; Neoplasms - enzymology; Oxidation-Reduction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.01.028

[Display omitted] Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5′-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3′-hydroxyl group and a 5′-deoxyribose phosphate moiety or activates the DNA-binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target.