Table 4.

Small Molecule Inhibitors of DNA Repair Proteins—Initiators.

Inhibitors Targeting	Enzymes	Pathways	Protein Target	Inhibitor	Mechanism of Action	Clinical Trial
ADP- ribosylation	PARP	DDR	PARP1, PARP2 and PARP3	Olaparib	Binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site [177].	2014: FDA approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer [183]. 2017: FDA approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572143.htm 2018: FDA approved for the treatment of adult patients with metastatic breast cancer who have a BRCA gene mutation. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm592347.htm
				Rucaparib	Binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site [177].	2016: FDA approved for treatment of adults patients with germline and/or somatic BRCA-mutated advanced ovarian cancer. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm533891.htm
			PARP1 and PARP2	Niraparib	Binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site and makes contact with the regulatory subdomains. Efficiently traps PARP1 on the damage-containing DNA [177].	2017: FDA approved for treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm548487.htm
				Veliparib	Binds within nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site and makes contact with the regulatory subdomains. Efficiently traps PARP1 on the damage-containing DNA [177].	Phase I-III clinical trials including patients with previously untreated advanced or metastatic squamous non-small cell lung cancer; patients receiving first cytotoxic chemotherapy for metastatic or advanced non-squamous, non-small cell lung cancer; patients with ovarian cancer; triple negative breast cancer; glioblastoma. Mostly in combination with chemotherapy. https://clinicaltrials.gov/ct2/results?term=Veliparib&age_v=&gndr=&type=&rslt=&phase=0&phase=1&phase=2&phase=3&Search=Apply
				Talazoparib	Binds within nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site and makes contact with the regulatory subdomains. Potent PARP trapping [177].	Phase I–III clinical trials including phase III patients with advanced and/or metastatic breast cancer with germline BRCA (breast cancer susceptibility gene) mutations and squamous cell lung carcinoma. https://clinicaltrials.gov/ct2/results?term=Talazoparib&age_v=&gndr=&type=&rslt=&phase=0&phase=1&phase=2&phase=3&Search=Apply
				CEP-9722	Binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site [177,179].	Phase I/II trial in patients with advanced or metastatic solid tumours and documented deficiencies of DNA repair pathways, such as BRCA1/2 (NCT01311713, NCT01345357, NCT00920595).
Phosphorylation	PIKK	DSB, cell cycle	ATM	KU-55933	Binds to the ATP binding pocket of ATM, blocking its kinase function and ATM-mediated signalling [170].	Pre-clinical development.
				KU-60019	Binds to the ATP binding pocket of ATM, blocking its kinase function and ATM-mediated signalling [184].	Pre-clinical development.
				KU-59403	Binds to the ATP binding pocket of ATM, blocking its kinase function and ATM-mediated signalling [185].	Pre-clinical development.
				CP466722	Binds to the ATP binding pocket of ATM, blocking its kinase function and ATM-mediated signalling [185].	Pre-clinical development.
				AZD0156	Binds to the ATP binding pocket of ATM, blocking its kinase function and ATM-mediated signalling [186].	Phase I trial of AZD0156 in combination with olaparib in patients with locally advanced/metastatic cancer: NCT02588105.
		SSB, Cell Cycle	ATR	VE-822/VX-970	Selectively inhibits ATR kinase activity and prevents ATR-mediated signalling in the ATR-checkpoint kinase 1 (Chk1) signalling pathway [187].	Phase I/II trial of VX970 and topotecan treating small cell lung cancer: NCT02487095. Phase I trial of VX970 in combination with veliparib and cisplatin in patients with advanced refractory solid tumours: NCT02723864 Phase I trial of VX970 and irinotecan hydrochloride in treating patients with metastatic cancer: NCT02595931.
				AZD6738	Selectively inhibits ATR kinase activity and prevents ATR-mediated signalling [188].	Phase I/II trial for AZD6738 in combination with acalabrutinib in subjects with relapse or refractory high-risk chronic lymphocytic leukaemia (CLL): NCT03328273. Phase I trial for AZD6738 in combination with palliative radiotherapy or chemotherapy in patients with advanced solid tumours: NCT02223923.
				BAY-1895344	Selectively inhibits ATR kinase activity and prevents ATR-mediated signalling in the ATR-checkpoint kinase 1 (Chk1) signalling pathway [189].	Phase I trial of BAY1895344 monotherapy in patients with advanced solid tumours and lymphomas: NCT03188965.
			ATR/CDK2	NU6027	Low micromolar inhibitor of ATR kinase activity and prevents ATR-mediated signalling in the ATR-checkpoint kinase 1 (Chk1) signalling pathway.	Pre-clinical development.