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.