Small‐molecule Inhibitors of DNA Base Excision Repair


Cells rely on several DNA (deoxyribonucleic acid) repair pathways to maintain the integrity of their genetic information, including DNA base excision repair (BER). BER involves the removal of a DNA base, damaged in some way by a chemical modification, and then subsequent repair to reconstitute the DNA. Inhibition of the proteins and enzymes that mediate BER can result in cell death, especially in actively dividing cells. As such, many of these enzymes are targets for pharmaceutical research to combat cancer and severe inflammatory ailments. Small molecules have been identified that inhibit at least three of the principal enzymes of BER: an enzyme that participates in the signalling of DNA damage, an endonuclease involved in processing an intermediate of BER and a DNA polymerase. This article focuses on the known BER enzyme inhibitors, many of which are pharmaceutical candidates in clinical trials to treat disease.

Key concepts:

  • Several small molecules have been developed that inhibit the enzymes involved in DNA base excision repair.

  • Inhibition of DNA base excision repair can sensitize cells to DNA‐damaging treatments.

  • Inhibitors of the DNA base excision repair enzymes are being investigated as potential treatments for cancer and severe inflammation.

Keywords: DNA repair; PARP; APE1; DNA polymerase β; cancer; chemotherapy

Figure 1.

Mechanisms of DNA base excision repair. A DNA glycosylase removes a damaged base. The enzyme apurinic/ (APE1) cleaves the abasic DNA strand. In short patch‐base excision repair (SPBER), DNA polymerase β (Pol β) inserts the appropriate deoxynucleotide and cleaves the deoxyribose phosphate (dRP) group before DNA ligase III (Lig III) and (XRCC1) resolve the structure. Poly(ADP‐ribose) polymerase (PARP1) also participates in this process. In long patch‐base excision repair (LPBER), DNA synthesis is carried out by a complex of several proteins, including DNA polymerases δ and ɛ (Pol δ/ɛ), replication factor C (RFC) and proliferating cellular nuclear antigen (PCNA). (FEN‐1) cleaves the displaced DNA strand, whereas DNA ligase I (Lig I) seals the DNA nick.

Figure 2.

The role of PARP in the cellular response to DNA damage. The enzyme poly(ADP‐ribose) polymerase (PARP) recognizes DNA damage caused by exogenous molecules and oxidative stress and signals for DNA repair. If the DNA damage is limited, PARP participates in the DNA repair process and allows cells to survive the insult. In cases of severe damage, PARP may become very hyperstimulated. Given that PARP uses the electron carrier molecule NAD+ as a substrate, a cell with overactive PARP will deplete its reserves of NAD+, and therefore ATP, which can lead to necrotic cell death. In either case, a small‐molecule inhibitor of PARP can lead to an apoptotic cell death by shutting down DNA metabolism (but not glycolytic metabolism).



Adhikari S, Choudhury S, Mitra PS et al. (2008) Targeting base excision repair for chemosensitization. Anti‐Cancer Agents in Medicinal Chemistry 8: 351–357.

Altmeyer M, Messner S, Hassa PO, Fey M and Hottiger MO (2009) Molecular mechanism of poly(ADP‐ribosyl)ation by PARP1 and identification of lysine residues as ADP‐ribose acceptor sites. Nucleic Acids Research 37: 3723–3738.

Bentle MS, Bey EA, Dong Y, Reinicke KE and Boothman DA (2006) New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors. Journal of Molecular Histology 37: 203–218.

Bowman KJ, White A, Golding BT, Griffin RJ and Curtin NJ (1998) Potentiation of anti‐cancer agent cytotoxicity by the potent poly(ADP‐ribose) polymerase inhibitors NU1025 and NU1064. British Journal of Cancer 78: 1269–1277.

Calabrese CR, Batey MA, Thomas HD et al. (2003) Identification of potent nontoxic poly(ADP‐ribose) polymerase‐1 inhibitors: chemopotentiation and pharmacological studies. Clinical Cancer Research 9: 2711–2718.

Fishel M and Kelley M (2007) The DNA base excision repair protein Ape1/Ref‐1 as a therapeutic and chemopreventive target. Molecular Aspects of Medicine 28: 375–395.

Fishel ML, He Y, Smith ML and Kelley MR (2007) Manipulation of base excision repair to sensitize ovarian cancer cells to alkylating agent temozolomide. Clinical Cancer Research 13: 260–267.

Frederick AM, Davis ML and Rice KP (2009) Inhibition of human DNA polymerase beta activity by the anticancer prodrug Cloretazine. Biochemical and Biophysical Research Communications 378: 419–423.

Hazan C, Boudsocq F, Gervais V et al. (2008) Structural insights on the pamoic acid and the 8 kDa domain of DNA polymerase beta complex: towards the design of higher‐affinity inhibitors. BMC Structural Biology 8: 22.

Helleday T, Petermann E, Lundin C, Hodgson B and Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nature Reviews. Cancer 8: 193–204.

Helleday T (2008) Amplifying tumour‐specific replication lesions by DNA repair inhibitors – a new era in targeted cancer therapy. European Journal of Cancer 44: 921–927.

Horvath EM, Benko R, Kiss L et al. (2009) Rapid ‘glycaemic swings’ induce nitrosative stress, activate poly(ADP‐ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus. Diabetologia 52: 952–961.

Hu HY, Horton JK, Gryk MR et al. (2004) Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping. Journal of Biological Chemistry 279: 39736–39744.

Ismail IS, Ito H, Mukainaka T et al. (2003) Ichthyotoxic and anticarcinogenic effects of triterpenoids from Sandoricum koetjape bark. Biological and Pharmaceutical Bulletin 26: 1351–1353.

Jiang YL, Krosky DJ, Seiple L and Stivers JT (2005) Uracil‐directed ligand tethering: an efficient strategy for uracil DNA glycosylase (UNG) inhibitor development. Journal of the American Chemical Society 127: 17412–17420.

Kelley MR and Fishel ML (2008) DNA repair proteins as molecular targets for cancer therapeutics. Anti‐Cancer Agents in Medicinal Chemistry 8: 417–425.

Khong HT, Dreisbach L, Kindler HL et al. (2007) A phase 2 study of ARQ 501 in combination with gemcitabine in adult patients with treatment naive, unresectable pancreatic adenocarcinoma. Journal of Clinical Oncology (Meeting Abstracts) 25: 15017.

Kimler BF, Schneiderman MH and Leeper DB (1978) Induction of concentration‐dependent blockade in the G2 phase of the cell cycle by cancer chemotherapeutic agents. Cancer Research 38: 809–814.

Lewis C and Low JA (2007) Clinical poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer. Current Opinion in Investigational Drugs 8: 1051–1056.

Luo MH and Kelley MR (2004) Inhibition of the human apurinic/apyrimidinic endonuclease (Ape1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone. Anticancer Research 24: 2127–2134.

Madhusudan S and Hickson ID (2005) DNA repair inhibition: a selective tumour targeting strategy. Trends in Molecular Medicine 11: 503–511.

Maga G and Hubscher U (2008) Repair and translesion DNA polymerases as anticancer drug targets. Anticancer Agents in Medicinal Chemistry 8: 431–447.

Martin SA, Lord CJ and Ashworth A (2008) DNA repair deficiency as a therapeutic target in cancer. Current Opinion in Genetics & Development 18: 80–86.

Pascucci B, Stucki M, Jonsson ZO, Dogliotti E and Hubscher U (1999) Long patch base excision repair with purified human proteins. DNA ligase I as patch size mediator for DNA polymerases delta and epsilon. Journal of Biological Chemistry 274: 33696–33702.

Peralta‐Leal A, Manuel Rodriguez‐Vargas J, Aguilar‐Quesada R et al. (2009) PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radical Biology and Medicine 47: 13–26.

Raffoul JJ, Sarkar FH and Hillman GG (2007) Radiosensitization of prostate cancer by soy isoflavones. Current Cancer Drug Targets 7: 759–765.

Roukos DH, Murray S and Briasoulis E (2007) Molecular genetic tools shape a roadmap towards a more accurate prognostic prediction and personalized management of cancer. Cancer Biology and Therapy 6: 308–312.

Seiple LA, Cardellina JH II, Akee R and Stivers JJ (2008) Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids. Molecular Pharmacology 73: 669–677.

Sharma RA and Dianov GL (2007) Targeting base excision repair to improve cancer therapies. Molecular Aspects of Medicine 28: 345–374.

Simeonov A, Kulkarni A, Dorjsuren D et al. (2009) Identification and characterization of inhibitors of human apurinic/apyrimidinic endonuclease APE1. PLoS ONE 4(6): e5740.

Southan GJ and Szabo C (2003) Poly(ADP‐ribose) polymerase inhibitors. Current Medicinal Chemistry 10: 321–340.

Szabó G, Soós P, Mandera S et al. (2004) Ino‐1001 a novel poly(ADP‐ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. Shock 21: 426–432.

Tentori L and Graziani G (2005) Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacological Research 52: 25–33.

Tentori L, Portarena I and Graziani G (2002) Potential clinical applications of poly(ADP‐ribose) polymerase (PARP) inhibitors. Pharmacological Research 45: 73–85.

Thomas HD, Calabrese CR, Batey MA et al. (2007) Preclinical selection of a novel poly(ADP‐ribose) polymerase inhibitor for clinical trial. Molecular Cancer Therapeutics 6: 945–956.

Yang S, Irani K, Heffron SE, Jurnak F and Meyskens FL Jr (2005) Alterations in the expression of the apurinic/apyrimidinic endonuclease‐1/redox factor‐1 (APE/Ref‐1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref‐1 inhibitor. Molecular Cancer Therapeutics 4: 1923–1935.

Zawahir Z, Dayam R, Deng J, Pereira C and Neamati N (2009) Pharmacophore guided discovery of small‐molecule human apurinic/apyrimidinic endonuclease 1 inhibitors. Journal of Medicinal Chemistry 52: 20–32.

Zou G and Maitra A (2008) Small‐molecule inhibitor of the AP endonuclease 1/REF‐1 E3330 inhibits pancreatic cancer cell growth and migration. Molecular Cancer Therapeutics 7: 2012–2021.

Further Reading

Lord CJ and Ashworth A (2008) Targeted therapy for cancer using PARP inhibitors. Current Opinion in Pharmacology 8(4): 363–369.

Nouspikel T (2009) DNA repair in mammalian cells. Cellular and Molecular Life Sciences 66(6): 994–1009.

Pal SK and Mortimer J (2009) Triple‐negative breast cancer: novel therapies and new directions. Maturitas 63(4): 269–274.

Reed AM, Fishel ML and Kelly MR (2009) Small‐molecule inhibitors of proteins involved in base excision repair potentiate the anti‐tumorigenic effect of existing chemotherapeutics and irradiation. Future Oncology 5(5): 713–226.

Sánchez‐Pérez I (2006) DNA repair inhibitors in cancer treatment. Clinical and Translational Oncology 8(9): 642–646.

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Praggastis, V Alexandra, and Rice, Kevin P(Mar 2010) Small‐molecule Inhibitors of DNA Base Excision Repair. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022212]