Table 8.

Small Molecule Inhibitors of DNA Repair Proteins—Chromatin Modification.

Inhibitors Targeting	Enzymes	Pathways	Protein Target	Inhibitor	Mechanism of Action	Clinical Trial
Acetylation	HDAC	Chromatin modification and DDR	Histone deacetylases (HDACs) I, IIa, IIb, IV	Vorinostat/SAHA	Inhibits HDAC by binding the zinc-activated catalytic site [352].	FDA approved (2006) for the treatment of cutaneous manifestations of T-cell lymphoma [352]. Phase III trial of vorinostat in the treatment of advanced malignant pleural mesothelioma and multiple myeloma: NCT00128102. Phase III trial in combination with chemotherapy for the treatment of advanced non-small cell lung cancer patients: NCT00473889.
			HDACs I, II	Belinostat	Inhibits HDAC by binding to the zinc-activated catalytic site [353].	FDA approved (2014) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma [353]. Phase I–II clinical trials in the treatment of a range of solid tumours, acute myeloid leukaemia, cutaneous T-cell lymphoma, lung and liver cancer and non-Hodgkins lymphoma and other haematological malignancies. https://clinicaltrials.gov/ct2/results?term=belinostat&age_v=&gndr=&type=&rslt=&Search=Apply
			HDACs I, II	Panobinostat	Inhibits HDAC by binding to the zinc-activated catalytic site [354].	FDA approved (2015) for the treatment of patients with multiple myeloma. https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm Phase I–III trials in the treatment of a range of cancers, including pancreatic, breast, lung, liver, prostate, thyroid, renal, colon, brain, gastric, skin, and haematological malignancies. https://clinicaltrials.gov/ct2/results?term=panobinostat+AND+Cancer+AND+Neoplasms&phase=0123
			HDACs 1,2,4,6	Romidepsin	inhibits HDAC by binding to the zinc-activated catalytic site [345].	FDA approved (2009) for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. 2011: FDA approved for the treatment of peripheral T-cell lymphoma in patients who have received at least one prior therapy [355].
			HDACs 1,2,3,10	Chidamide	Inhibits HDAC by binding to the zinc-activated catalytic site [356].	Phase III trial in combination with exemestane for the treatment of hormone-receptor positive advanced breast cancer: NCT02482753. Phase III trial in combination with chemotherapy for the treatment of peripheral T-cell lymphoma: NCT03023358.
			HDACs I, IIa	Valproic acid (VPA)	In vivo and in vitro induces differentiation of transformed cells and can delay growth in primary tumours [350,351,357,358].	Enrolled in >80 clinical cancer trials, including five in phase III (for multiple tumour types). https://clinicaltrials.gov/ct2/results?cond=Cancer&term=Valproic+acid&cntry=&state=&city=&dist=
	histone acetyl transferases (HAT)		p300/CBP, PCAF, Tip60	Curcumin	Inhibits p300/CBP by decreasing the binding efficiency of both histones and acetyl CoA to p300 [359].	Phase I–III clinical trials for the treatment of multiple tumour types. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=Curcumin+&cntry=&state=&city=&dist=
			p300, CBP, Tip60, PCAF	EGCG	Did not appear bind to the HAT domain, potentially binds another site on the protein [357].	Phase I–IV clinical trials in a range of tumours including breast, prostate, colon, lung, pancreas. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=EGCG&cntry=&state=&city=&dist=
			Tip60	TH1834	Binds into the AcCoA binding pocket [360].	Pre-clinical development.
			Tip60	NU9056	Binds into the AcCoA binding pocket [361].	Pre-clinical development.
			PCAF, Gcn5, p300 CREB	PU139	Predicted to bind at the catalytic site binding pocket [362].	Pre-clinical development.
			CBP, p300	PU141	Predicted to bind at the catalytic site binding pocket [362].	Pre-clinical development.
			PCAF, Gcn5	CPTH6	Competes with Acetyl-CoA to bind at the catalytic site [363].	Pre-clinical development.
			p300	RTK1	Through its hydroxyl group, possibly forms a specific interaction with lysine residue (Lys-1358) in the p300 HAT domain [364].	Pre-clinical development.
Methylation	KMT		DOT1-L	EPZ-5676	Occupies the S-adenosyl methionine (SAM) binding pocket of DOT1-L [365].	Phase I trial for the treatment of acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL): NCT02141828.
			G9a	UNC0638	Occupies the histone peptide-binding channel and interacts with the lysine-binding pocket [366].	Pre-clinical development.
			EZH2	EPZ-6438 (tazemetostat)	Occupies the S-adenosyl methionine (SAM) binding pocket of EZH2 [367].	Phase I–II clinical trials for the treatment of recurrent ovarian, primary peritoneal, or endometrial cancer, different types of lymphomas, sarcomas and advanced solid tumours. https://clinicaltrials.gov/ct2/results?term=EPZ-6438&age_v=&gndr=&type=&rslt=&phase=0&phase=1&phase=2&phase=3&Search=Apply
			SMYD2	AZ505	Inhibits though its benzooxazinone group, which is positioned within the lysine-binding channel of the substrate [368].	Pre-clinical development.
			SETD8	Nahuoic acid A	Occupies the S-adenosyl methionine (SAM) binding pocket [369].	Pre-clinical development.
			SETD8	Peptide based inhibitors	Selective norleucine containing peptide inhibitor [370]	Pre-clinical development.
	KDM		LSD1	TCP (tranylcypromine)	Inhibits LSD1 by forming a covalent adduct with the FAD cofactor [371].	Phase I/II trial in combination with ATRA (all-trans-retinoic acid) for the treatment of acute myeloid leukaemia or myelodysplastic syndrome (NCT02717884, NCT02273102).
				GSK2879552	Inhibits LSD1 by forming a covalent adduct with the FAD cofactor, leading to homolytic cleavage of the cyclopropyl ring [372].	Phase I trial for the treatment of myelocytic leukaemia (NCT02177812) and small cell carcinoma (NCT02034123). Phase II trial in combination with azacitidine for the treatment of myelodysplastic syndrome: NCT02929498.