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. Author manuscript; available in PMC: 2015 Mar 1.
Published in final edited form as: Future Oncol. 2014 May;10(7):1215–1237. doi: 10.2217/fon.14.60

Table 3.

Base excision repair inhibitors in development and clinical use.

BER protein Function(s) Rationales for inhibiting Challenges Compounds being investigated
APE1 Repair: prepares AP site to receive new nucleotide(s)
Redox: maintains genes in their active, reduced state
Overexpressed in many cancers
Associated with resistance to alkylating and oxidizing agents
No substitute exists for this protein
Achieving specificity to solely inhibit the repair or redox function Repair:
• Nonspecific: methoxyamine (binds to the aldehyde in the AP site of DNA); lucanthone
• Specific: AR03; lnhibitor-1; ML-199 and analogs
Redox:
• E3330and analogs

Pol β Resynthesizes nucleotides
Removes certain blocking residues
A rate-limiting step in BER Often overexpressed in tumor cells
Associated with resistance to IR, bleomycin, some alkylating agents, cisplatin
Difficult to develop an inhibitor specific to the polymerase domain that would not also inhibit polymerases involved in DNA replication
Inhibiting its lyase function may be more lucrative
>60 inhibitors identified; most lack specificity
Most promising so far (cell studies only):
• Oleanolicacid
• Edgeworin
• Betulinic
• Stigmasterol
•NCS-666715
•NSC-124854

FEN1 Progressivity factor Helps polymerases synthesize nucleotides efficiently and accurately Elevated in many cancers Inhibition creates unligatable DNAand makes cells hypersensitive to alkylating agents Importance of protein in pathway could prove difficult in identifying inhibitors with lowtoxicity to normal cells Afewhydroxyurea-based FEN1 inhibitors (cell studies only)

PARP1 Surveillance/damage sensor
Assesses extent of damage; determines whether to signal apoptosis Helps decondense chromatin
Recruits repair proteins to the damage site Facilitates repairs
Uses NAD+to transfer ADP-ribose polymers onto specific acceptor proteins including itself; this modifies the protein's properties Although not essential to BER, PARPI's absence causes an accumulation of DNA damage that certain cancers cannot repair Inhibitors potentiate the effects of alkylating agents, platinating agents, topoisomerase 1 poisons, IR Secondary mutations can correct for this repair deficiency, causing resistance to PARPis Already in clinical use:
• Iniparib
• Olaparib
In clinical trials:
• ABT-888
• AZD2461
•BMN673
• E7449
• INO-1001
• CEP-9722
• MK-4827
• Rucaparib
• Velaparib
• >115 clinical trials in progress for newer-generation PARPis and broader use of first-generation inhibitors
Cell studies only:
• PJ-34
•DPQ

AP: Abasic (apurinic, apyrimidinic); BER: Base excision repair; IR: Ionizing radiation; PARPi: PARP inhibitor.