Table 1.
Inhibitors of the DDR pathway that reached clinical trials.
| Cancer | Mechanism | Clinical Trial/Phase | Ref. | |
|---|---|---|---|---|
| Inhibitors of PARP | ||||
| Olaparib (Lynparza; AZD-2281) Phase 4 |
Approved for BRCAMut metastatic BC (2018), advanced OC (2014), PC (2019) and prostate cancer (2020); advanced gastric and metastatic renal cell carcinoma | PARP1/2/3 inhibitor; binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site; synthetic lethality with HR defects, sensitizes cells to radiation and DNA damaging agents |
NCT03344965/II NCT02184195/III NCT01924533/III NCT02810743/III NCT03286842/III NCT03786796/II NCT01874353/III |
[104,105] |
| Rucaparib (AG-01499; Clovis) Phase 3 |
Approved for advanced OC (2016) and BRCAMut prostate cancer (2020); Solid tumours (e.g., PC and metastatic urothelial cancer) |
NCT04171700/II NCT02975934/III NCT02042378/II NCT02678182/II NCT03533946/II NCT03413995/II |
[20] | |
| Niraparib (MK-4827; Zejula; Tesaro) Phase 3 |
Approved for recurrent OC (2017); BC, OC and PC with BRCAMut; lung, head and neck cancer | PARP1/2 inhibitor; binds within the nicotinamide-binding pocket in the ADP-ribosyl transferase catalytic site, contacting with the regulatory subdomains; traps PARP to DNA damage sites; Talazoparib is effective in both BRCAMut and PTENMut cancer cells |
NCT01905592/III NCT03601923/II NCT03553004/II NCT03016338/II NCT03431350 I/II NCT03891615/I |
[106,107] |
| Veliparib (ABT-888; Abbvie) Phase 3 | Metastatic BRCAMut BC; NSCLC; HGSOC |
NCT02163694/III NCT01149083/II NCT01657799/II NCT02890355/II NCT03044795/III NCT02158507/NA |
[98] | |
| Talazoparib (BMN 673) Phase 3 | Approved for BRCAMut locally advanced or metastatic BC (2018); BRCA1Mut OC; leukaemia |
NCT02401347/II NCT02326844/II NCT02282345/II NCT02401347/II NCT03148795/II NCT03426254/I |
[97] | |
| INO-1001 Phase 2 |
Melanoma | Potent PARPi | NCT00272415/I | [99] |
| Pamiparib (BGB-290) Phase 3 |
Advanced solid tumours; OC; TNBC; prostate, brain and central nervous system tumours | Potent and selective inhibitor of PARP1 and PARP2 |
NCT03933761/II NCT03991494/II NCT03712930/II NCT04164199/III NCT03150862 I/II NCT03333915 I/II |
[100] |
| E7449 (2x-121) Phase 2 |
Advanced OC; TNBC; metastatic BC; malignant solid tumours | Dual inhibitor of PARP1/2 (traps PARP1 onto damaged DNA sites) and tankyrase 1/2. |
NCT03878849/II NCT01618136 I/II NCT03562832/II |
[101] |
| Inhibitors of ATM | ||||
| M-3541 | Solid tumours | Compete with ATP-binding site of ATM, inhibiting its catalytic function in DDR. KU-60019: downregulates pAKT reducing cell survival; combined with CDDP increases γH2AX and reduces RAD51 foci; specific for PTEN-deficient and p53Mut cells upon IR. AZD-0156/AZD-1390: improved blood-brain barrier penetration |
NCT03225105/I | [108] |
| AZD-0156 | Advanced solid tumours | NCT02588105/I | [109] | |
| AZD1390 | Glioblastoma; brain neoplasms |
NCT03215381/I NCT03423628/I |
[110] | |
| KU-60019 | Kidney Cancer | NCT03571438/NA | [111] | |
| Dual inhibitors of PI3K/mTOR | ||||
| NVP-BEZ235 | Prostate cancer; advanced tumours including metastatic BC | Blocks ATM/ATR/DNA-PKs activity; induces chemo- and radio-sensitization, particularly in RAS-overexpressing tumours | NCT01717898I/II NCT01634061/I NCT01288092/II NCT01856101/II NCT01495247I/II |
[112,113,114] |
| Inhibitors of ATR | ||||
| AZD6738 (ceralasertib) | Advanced solid tumours; lymphomas | Selective ATR inhibitor; phosphorylates Chk1 and increases γH2AX; promising with carboplatin or IR; antitumor activity in ATM-deficient xenograft models |
NCT03770429/I NCT03682289/II NCT02630199/I NCT03462342/II NCT04298008/II NCT04361825/II |
[22] |
| BAY1895344 | ATR selective inhibitor |
NCT04095273/I NCT03188965/I NCT04267939/I |
[115] | |
| VX-803 (M-4344) |
NCT04149145/I NCT02278250/I |
[115] | ||
| VX-970 (Berzosertib; M6620, VE-822) | Sensitizes PC and NSCLC cells to chemo- and radiotherapy; no toxicity in normal cells/tissues |
NCT03718091/II NCT02487095 I/II NCT03641547/I NCT04052555/I NCT02157792/I NCT02627443 I/II |
[116] | |
| Inhibitors of Chk1/Chk2 | ||||
| UCN-01 | Advanced solid tumours | Block Chk1/2 activity by binding to ATP-binding pocket; induce cell cycle arrest in G1 (UCN-01) or G2 (MK8776) phases and apoptosis |
NCT00082017/II NCT00072189/II NCT00045747/II NCT00072267/ II |
[117] |
| GDC-0425 | NCT01359696/I | [118] | ||
| MK-8776 (SCH900776) |
NCT00779584/I NCT01521299/I NCT01870596/II NCT00907517/I |
[119] | ||
| SRA-737 | NCT02797964I/II NCT02797977I/II |
|||
| AZD7762 | Inhibits Chk1/2 by interaction with their ATP-binding pocket; suppresses pCdc25C |
NCT00937664/I NCT00413686/I NCT00473616/I |
[120] | |
| CBP-501 | Inhibits kinases (MAPKAP-K2, C-TAK1, Chk1) that phosphorylate Cdc25C Ser216 |
NCT00551512/I NCT00942825/II NCT03113188/I NCT00700336I/II |
[121] | |
| Rabusertib (LY2603618) | Solid tumours (NSCLC; PC) | Chk1 selective inhibitor |
NCT00415636/I NCT00839332I/II NCT00988858/II NCT01296568/I NCT01139775I/II |
[119] |
| Prexasertib (LY-2606368) | SCLC, OC, TNBC, metastatic castrate-resistant PC | Dual Chk1/2 inhibitor |
NCT01115790/I NCT02873975/II NCT02203513/II NCT02808650/I NCT02514603/I |
|
| Inhibitors of WEE-1 | ||||
| MK-1775 (AZD-1775) | NSCLC; advanced acute MM; OC; TNBC; PC; head and neck cancer; gastric cancer | Inhibitor of WEE1/2 and PLK1 kinases; potent in combination therapy |
NCT01164995/II NCT02610075/I NCT01076400I/II NCT02087241/II NCT03012477/II |
[122] |
| DNA-PK inhibitors (NHEJ pathway) | ||||
| LY-3023414 | Prostate cancer and endometrial; NSCLC; TNBC; PC; lymphoma | Potent and selective ATP competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK |
NCT02549989/II NCT04032080/II NCT02575703/I NCT02549989/II NCT02443337/II |
[123] |
| CC-122 | Melanoma; advanced solid cancer; relapsed or refractory B-cell malignancies |
NCT03834623/II NCT03310619I/II NCT02323906/I NCT02509039/I NCT01421524/I |
[124,125,126] | |
| CC-115 | Glioblastoma; PC; Head and neck squamous cell carcinoma |
NCT02833883/I NCT01353625/I NCT02977780/II |
||
| M-3814 (MSC2490484A) | Various solid malignancies | DNA-PK-dependent inhibitor |
NCT03116971/I NCT03724890/I NCT04172532I/II NCT04092270/I NCT02516813/I NCT02316197/I |
[127,128] |
| AZD7648 | NCT03907969I/II | [129] | ||
| VX-984 (M9831) | NCT02644278/I | [127,128] | ||
| Dual inhibitors of HR and NHEJ | ||||
| AsiDNA | Various solid malignancies | Prevents recruitment of repair enzymes (required for HR and NHEJ) at DSBs: acts as bait for DNA repair proteins or induces false DNA damage signalling | NCT03579628/I | [130] |
| Inhibitors of RAD51 recombinase (HR pathway) | ||||
| CYT-0851 | B-Cell malignancies; advanced solid tumours | Reduces RAD51 migration to DNA damage sites | NCT03997968I/II | [131] |
Clinical data obtained from clinicaltrials.gov (accessed on 14 May 2021); breast cancer (BC); triple-negative breast cancer (TNBC); ovarian cancer (OC); pancreatic cancer (PC); non-small cell lung cancer (NSCLC); small cell lung carcinoma (SCLC); myeloid leukaemia (MM); high grade serous ovarian carcinoma (HGSOC); ionizing radiation (IR); cisplatin (CDDP); phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); mammalian target of rapamycin (mTOR); DNA-dependent protein kinase (DNA-PK); transforming growth factor-beta-activated kinase 1 (TAK1); polo-like kinase 1 (PLK1); not applicable (NA).