Table 6.
Small Molecule Inhibitors of DNA Repair Proteins—NHEJ.
| Inhibitors Targeting | Enzymes | Pathways | Protein Target | Inhibitor | Mechanism of Action | Clinical Trial |
|---|---|---|---|---|---|---|
| Phosphorylation | PIKK | NHEJ | DNA-PKcs | NU7026 | A potent inhibitor of DNA-PK, exhibiting ATP-competitive inhibitor kinetics [264]. | Pre-clinical development. |
| NU7441 | A highly potent and selective DNA-PK inhibitor, exhibiting ATP-competitive inhibition kinetics [263]. | Pre-clinical development. | ||||
| VX-984/M9831 | ATP-competitive inhibitor of DNA-PKcs [269]. | Phase 1 clinical trial as a single agent and in combination with doxorubicin or pegylated liposomal doxorubicin (PLD): NCT02644278. | ||||
| MSC-2490484A/M3814 | Binds to DNA-PK and inhibits its kinase activity and prevents (at least partially) the NHEJ pathway [266]. | Phase I trial of MSC2490484A monotherapy in subjects with advanced solid tumors or chronic lymphocytic leukaemia (CLL) likely to have alterations in DNA repair mechanisms, such as the BRCA and ATM pathways: NCT02316197. Phase I trial of MSC2490484A in combination with radiotherapy and in combination with chemoradiotherapy (radiotherapy and cisplatin) in patients with advanced solid tumours: NCT02516813. |
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| DNA processing | DNA ligase | Ligases I, III and IV | L189 | Equally inhibits ligases I, III and IV by blocking DNA binding [253]. | Pre-clinical development. | |
| Ligase-IV (DNA ligases I and III) |
SCR7 | Binds to the DNA-binding domain of ligase-IV, thus preventing the binding of ligase IV to DNA ends [271]. | Pre-clinical development. |