Table 2.
DDR inhibitors under pre-clinical studies.
| Mechanism | Research Model | Ref. | |
|---|---|---|---|
| Inhibitors of RAD51 Recombinase (HR Pathway) | |||
| DIDS | Binds directly to RAD51; inhibits ssDNA- and dsDNA-binding, and joint molecule formation in DNA strand exchange assays; stimulates ATP hydrolysis; in vitro toxicity |
In vitro DNA repair biochemical assays |
[153] |
| B02 | Inhibits RAD51-mediated ssDNA-binding activity; enhances cells sensitivity to IR, MMC, PARPi, doxorubicin and CDDP by inhibiting RAD51-dependent DSBs repair |
In vitro DNA repair biochemical assays; mouse orthotopic xenograft of human TNBC |
[154,159,160] |
| RI-1 | Covalently binding to RAD51 protein, surface stably and irreversibly inhibiting its filament formation upon DNA damage; inhibit HR and disrupts DNA damage-induced RAD51 foci formation; sensitizes cancer cells to MMC | In vitro DNA repair biochemical assays; human embryonic kidney, ECC, BC and OS cell lines |
[155,156] |
| RI-2 | |||
| IBR2 IBR120 |
Disrupt RAD51-binding to BRCA2 and RAD51 oligomerization; sensitize cancer cells to IR | In vitro DNA repair biochemical assays; BC xenograft model; imatinib-resistant T315I-Ba/F3 cells |
[151] |
| Chicago Skye Blue (CSB) | Prevents RAD51 nucleoprotein filament formation by interfering with the RAD51 binding to ssDNA | In vitro DNA repair biochemical assays |
[157] |
| Inhibitors of RAD52 (HR pathway) | |||
| 6-Hydroxy-d,l-dopa | Disrupts RAD52 oligomerization | In vitro DNA repair biochemical assays; BC and PC cell lines | [161] |
| D-103 | Inhibit RAD52-mediated ssDNA annealing; tested in BRCA1Mut and BRCA2Mut cells | In vitro DNA repair biochemical assays; BC, OC, PC and OS cell lines | [162] |
| D-G23 | |||
| AICAR 5′-phosphate(ZMP) |
Disrupts the RAD52-ssDNA interaction; targets intracellular RAD52; undergoes phosphorylation in the cytoplasm, preferentially killing BRCA1Mut and BRCA2Mut cells | In vitro DNA repair biochemical assays; BRCA1-deficient BCR-ABL1-32Dcl3 murine hematopoietic cells expressing GFP-RAD52; BC, PC and OS cell lines | [163] |
| (-)- EGC | Specifically bind to RAD52; disrupt the RAD52-ssDNA interaction and its annealing activity; kill BRCA2Mut cells | In vitro DNA repair biochemical assays; human fibroblasts |
[164] |
| NP-004255 | |||
| Inhibitor of the BRCA1-BARD1 interaction (HR pathway) | |||
| BBIT20 | Disrupts the BRCA1-BARD1 interaction | Co-immunoprecipitation and immunofluorescence assays; BC and OC cell lines; patient-derived cells and xenograft mouse models of OC |
[165] |
| Inhibitor of RAD54 DNA Branch Migration Activity (HR pathway) | |||
| Streptonigrin | Directly binds to RAD54 and inhibits its ATPase by reactive oxygen species generation | In vitro DNA repair biochemical assays |
[166] |
| Inhibitors of WRN DNA Helicase | |||
| NSC 19630 | Specifically inhibits WRN helicase activity, but not its nuclease activity; increases cellular sensitivity to PARPi |
In vitro DNA repair biochemical assays; human ECC, RC, CC, OC, BC and leukaemia cell lines |
[167] |
| NSC 617145 | Specifically inhibits WRN helicase activity, but not its nuclease activity; likely traps WRN on the DNA substrate |
In vitro DNA repair biochemical assays; human ECC, OS and CC cell lines |
[168] |
| Inhibitor of BLM DNA Helicase | |||
| ML216 | Inhibits helicase activity of BLM by disruption of its binding to DNA; inhibits WRN | In vitro DNA repair biochemical assays; BLM-complemented (PSNF5) and BLM-deficient (PSNG13) fibroblast cell line |
[169] |
| Inhibitors of MRE11 Endo- and Exonuclease | |||
| Mirin | Bind to active sites of MRE11, blocking DNA phosphate backbone rotation and inhibiting its exonuclease activity; inhibit MRN/DSBs-mediated ATM activation not affecting ATM protein kinase activity; G2/M-phase progression in HR-deficient cells | In vitro DNA repair biochemical assays; human OS cell line; human primary fibroblasts, NHEJ-deficient cells and FA cell lines |
[170,171] |
| PFM39 | |||
| PFM01 PFM03 |
Bind near the dimer interface, blocking the ssDNA-binding path and disrupting endonuclease activity; enhance NHEJ while reducing the HR pathway (no DDR defects associated) | In vitro DNA repair biochemical assays; human primary fibroblasts, NHEJ-deficient cells and FA cell lines |
[171] |
Cisplatin (CDDP); ionizing radiation (IR); mitomycin C (MMC); triple-negative breast cancer (TNBC); wild-type (wt); werner syndrome helicase (WRN); bloom syndrome protein (BLM); breast cancer (BC); pancreatic cancer (PC); endocervical cancer (ECC); ovarian cancer (OC); osteosarcoma (OS); colon cancer (CC); renal cancer (RR); fanconi anemia (FA).