Table 5.

Small Molecule Inhibitors of DNA Repair Proteins—Effectors.

Inhibitors Targeting	Enzymes	Pathways	Protein Target	Inhibitor	Mechanism of Action	Clinical Trial
DNA processing	RecQ DNA Helicases	DDR	BLM	ML216	Inhibits helicase activity of BLM. ML216 competes with ATP binding, the driving force behind its DNA unwinding, or by preventing BLM from binding to DNA [218].	Pre-clinical development.
			WRN	NSC 617145	Inhibits WRN helicase activity, but not its nuclease activity. Thought to trap WRN on the DNA substrate [219].	Pre-clinical development.
				NSC 19630	Inhibits helicase activity, but not nuclease activity [221].	Pre-clinical development.
	Topoisomerases	DDR, DNA replication	TOP1	Irinotecan	Prevents religation of the DNA strand by binding to topoisomerase I-DNA complex [226].	FDA approved (1996) for treatment of colorectal cancer when disease has recurred following initial fluorouracil treatment. FDA approved (2015) in combination with fluorouracil and leucovorin, in patients with advanced (metastatic) pancreatic cancer previously treated with gemcitabine-based chemotherapy. https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm
				Topotecan	Binds to the topoisomerase I-DNA complex and prevents re-ligation of single strand breaks [226].	FDA approved (2006) in combination with cisplatin for the treatment of stage IVB recurrent or persistent cervical cancer that is not amenable to curative treatment with surgery and/or radiotherapy. https://www.cancer.gov/about-cancer/treatment/drugs/fda-topotecan-hydrochloride Phase III trial in combination with radiotherapy in patients with brain metastases from non-small cell lung cancer: NCT00390806.
				Indotecan (LMP400)	Binds to the topoisomerase I-DNA covalent cleavage complexes, and inhibits repair of single-strand breaks [223].	Phase I trial of LMP400 in subjects with solid tumours or lymphomas that have not responded to treatment: NCT01794104.
				Indimitecan (LMP776)	Preferential Top1-DNA trapping at unique sites [232].	Phase I trial in adults with relapsed solid tumors and lymphomas: NCT01051635.
				GENZ-644282	Binds to the topoisomerase I-DNA covalent cleavage complexes, and inhibits repair of single-strand breaks [228].	Phase I trial of Genz-644282 in patients with advanced malignant, solid tumours: NCT00942799.
			TOP2	Doxorubicin	Intercalates into DNA and targets the topoisomerase II cleavage complexes, thereby inhibiting DNA religation [223].	FDA approved (1974) and currently used for treatment for acute lymphoblastic leukaemia, acute myeloblastic leukaemia, Wilms’ tumour, neuroblastoma, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma [233].
				Etoposide	Intercalates into DNA and poisons the topoisomerase II cleavage complexes, thereby inhibiting DNA re-ligation [223].	FDA approved (1983) and currently used in combination with other chemotherapeutic drugs for treatment of patients with refractory testicular tumours, small lung cancer, ovarian cancer, leukaemia and lymphoma. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=074290
				Mitoxantrone	Intercalates into DNA, causing crosslinks and strand breaks and targets the topoisomerase II cleavage complexes, thereby inhibiting DNA re-ligation [223].	FDA approved (1987) and currently used with other drugs to treat acute myeloid leukaemia and prostate cancer. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=077356 https://www.cancer.gov/about-cancer/treatment/drugs/mitoxantronehydrochloride
				Aclarubicin	Intercalates into DNA and targets the topoisomerase II cleavage complexes, inhibiting DNA re-ligation [223].	Phase II–IV trials in combination with other drugs in patients with acute myeloid leukaemia (AML). https://clinicaltrials.gov/ct2/results?cond=cancer&term=Aclarubicin&cntry=&state=&city=&dist=
				Dexrazoxane (ICRF-187)	Catalytic TOP2 inhibitor.	Phase III–IV trials against multiple cancers. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=Dexrazoxane&cntry=&state=&city=&dist=&Search=Search
DNA repair signalling	MRN complex	DDR	Mre11	Mirin	Binds in the active site of Mre11 blocking DNA phosphate backbone rotation; inhibits exonuclease activity of Mre11 and MRN/DSB-mediated ATM activation without affecting ATM protein kinase activity [234].	Pre-clinical development.
				PFM01	Binds near the dimer interface blocking the ssDNA-binding path towards the catalytic metal ions and disrupts endonuclease activity [185].	Pre-clinical development.
				PFM39	Binds in the active site of Mre11 inhibiting its exonuclease activity [185].	Pre-clinical development.
DNA repair	Nucleotide Excision Repair (NER)		ERCC1–XPF	E-X AS5-4	Targets the ERCC1–XPF interaction domain for heterodimerisation [235].	Pre-clinical development.
				E-X AS7	Targets the XPF active site itself [235].	Pre-clinical development.