Table 5.

Nucleotide excision repair inhibitors in development.

NER protein	Function(s)	Rationales for inhibiting	Challenges	Compounds being Investigated
NER pathway†		UCN-0l1 and trabectedin affect multiple NER proteins Inhibition decreases the interaction of XPA and ERCC1, as well as other proteins with kinase activity F11782 isatopoisomerase inhibitor with yet-to-be-defined NER activity	Complexity and importance of pathway in normal cells could complicate development and determination of therapeutic window	Phase I and II trials:
				• UCN-01
				• Trabectedin
				Cell studies:
				•F11782
XPA	Stabilizer Positions endonucleases for excision	Its only known role is in NER Not highly expressed; likely a rate-limiting repair factor	Complexity of the network of protein interactions involved Chemical similarities in binding pockets of proteins complicates the development of protein-specific inhibitors	Indirectly; see XPF/ERCC1 discussion
RPA	Scaffolding protein Stabilizer	Is essential to NER RPA mutations are linked to development of cancer	Complexity of the network of protein interactions involved Chemical similarities in binding pockets of proteins complicates the development of protein-specific inhibitors	Cell studies:
				• MCI13E and MCI13F
				• TRDL-505
XPF/ERCC1	Endonuclease	Its only known role is in NER Overexpressed in cisplatin-resistant cancers	Complexity of the network of protein interactions involved Chemical similarities in binding pockets of proteins complicates the development of protein-specific inhibitors	In silico:
				• NERI01

Noncatalytic aspects of NER (protein-protein and protein-DNA interactions, nnodulation of transcription regulation) nnay be nnore viable targets for inhibition, as seen in the effect ofachimeric IgGI nnonoclonal antibody on reducing XPF/ERCC1 expression.

^†MuItiple proteins within NER are inhibited; which ones are still being researched.

NER: Nucleotide excision repair.

Adapted with permission fronn [28].