Table 7.

Nonhomologous end joining inhibitors in development.

NHEJ protein	Function(s)	Rationales for inhibiting	Challenges	Compounds being investigated
DNA-PK	Processes incompatible ends so they can be ligated	Appears to be unique to NHEJ Essential for NHEJ activity	Increases DNA damage tolerance Causes chemoresistance Predisposes cells to autosomal recessive disorders and malignancies, especially lymphoid cancers	Nonspecific (inhibit PI3K):
				• Wortmannin LY294002 DNA-PK-specific (cell studies only):
				• NU7441
				• NU7026
				Phase I studies:
				• CC-115
				• CC-122
PNKP	Processes incompatible ends so nucleotidescan be replaced and the termini ligated	Appears to be unique to NHEJ	Increases DNA damage tolerance Causes chemoresistance Predisposes cells to autosomal recessive disorders and malignancies, especially lymphoid cancers	Cell studies only:
				• A12B4C3
Ligase IV	Seals nicks in final repair step	A rate-limiting step Cannot work in the absence of XRCC4	Increases DNA damage tolerance Causes chemoresistancePredisposes cells to autosomal recessive disorders and malignancies, especially lymphoid cancers	Murine models:
				• SCR7

Indirect ways of modulating NHEJ functionality are being explored as more viable options than direct inhibition. Examples: overexpression of a truncated form of XRCC4 can inhibit NHEJ by interfering with DNA Ligase IV; DNA-PKcs can be inhibited indirectly by inhibiting EGFR or by inhibiting ATM (by using miRNA or small-molecule inhibitors); topoisomerase inhibitors prevent NHEJ repair proteins from gaining access to areas of damage; and epigenetic factors (methylation of gene promoters) are under investigation as well. It is yet unknown how or if these findings can translate into future clinical use.

NHEJ: Nonhomologous end joining.

Adapted with permission from [28].