TY - JOUR

T1 - Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1)

AU - Laev, Sergey S.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Apurinic/apyrimidinic (AP) site

KW - Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1)

KW - Base excision repair (BER)

KW - DNA repair

KW - E3330

KW - Inhibitors

KW - Lucanthone

KW - Methoxyamine

KW - BASE-EXCISION-REPAIR

KW - APURINIC-APYRIMIDINIC ENDONUCLEASE

KW - FACTOR-I

KW - SIGNALING PROTEIN APE1/REF-1

KW - ABASIC ENDONUCLEASE

KW - SMALL-MOLECULE INHIBITOR

KW - DNA-BINDING ACTIVITY

KW - CELL LUNG-CANCER

KW - HUMAN AP ENDONUCLEASE-1

KW - NF-KAPPA-B

KW - Humans

KW - DNA Repair/drug effects

KW - Enzyme Inhibitors/chemistry

KW - Oxidation-Reduction

KW - Neoplasms/drug therapy

KW - DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors

KW - Antineoplastic Agents/chemistry

KW - Animals

KW - Cell Line, Tumor

UR - http://www.scopus.com/inward/record.url?scp=85011068071&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2017.01.028

DO - 10.1016/j.bmc.2017.01.028

M3 - Review article

C2 - 28161249

AN - SCOPUS:85011068071

VL - 25

SP - 2531

EP - 2544

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 9

ER -