Table 1.
Summary of ATR inhibitors in preclinical and/or clinical development.
| Agent | Specificity [Primary Targets] | ATR Selectivity [Fold] |
|---|---|---|
| Preclinical development | ||
| Schisandrin B | ATR IC50 = 7.25 μM | Not reported |
| NU6027 | ATR; Ki = 0.1 μM CDK2; Ki = 1.3 μM CDK1; Ki = 2.5 μM |
ATM homologs > 1.5 |
| Dactolisib (NVP-BEZ235) | ATR; IC50 = 21 nM ATM; IC50 = 7 nM DNA-PK; IC50 = 5 nM mTOR; IC50 = 2 nM PI3K; IC50 = 2 nM |
No selectivity |
| EPT-46464 | ATR; IC50 = 14 nM mTOR; IC50 = 0.6 nM | ATM > 40, DNAPK > 2.5 PI3K > 12 |
| Torin 2 | ATR; IC50 < 10 nM mTOR; IC50 = 0.25 nM | No selectivity |
| VE-821 | ATR; IC50 = 26 nM | ATR homologs > 100 PI3K > 100 |
| AZ20 | ATR; IC50 = 5 nM | ATM, DNA-PK, PI3K > 600 mTOR ≤ 8 |
| Novartis's Tetrahydropyrazolo[1,5-a] pyrazines lead |
ATR; IC50 = 0.4 nM | ATM, DNA-PK, PI3K > 4000 mTOR > 100 |
| Novartis's Azabenzimidazole series lead |
ATR; IC50 = 0.5 nM | ATR homologs, PI3K > 30,000 |
| Clinical – Phase I | ||
| M4344 (VX-803) | ATR; IC50 < 0.2 nM | ATR homologs, PI3K > 100 |
| BAY1895344 | ATR; IC50 = 7 nM | ATM > 200 DNA-PK > 40 PI3K > 400 mTOR ≥ 6 mTORcellular > 60 |
| Clinical – Phase I & II | ||
| Berzosertib [M6620 (VX-970)] | ATR; IC50 = 0.2 nM | ATR homologs, PI3K > 100 |
| Ceralasertib [AZD6738] | ATR; IC50 = 4 nM | ATR homologs, PI3K > 300 |