Table 4. Profile of the Selected Compounds against the PARP Enzymes, IC50 (pIC50 ± SEM, n = 3), where Mono-ARTs PARP7-PARP16 are Measured Using a Proximity-Enhanced Assay,47 Potency of the Compounds in Rescuing Cells from PARP10 Overexpression along with 95% Confidence Interval for the EC50, and ADME Profiling.
| 16 (OUL245) | 21 (OUL243) | 27 (OUL232) | |
|---|---|---|---|
| Profiling of PARP and TNKS Enzymes | |||
| PARP1 | 570 nM(6.25 ± 0.02) | 1.6 μM(5.79 ± 0.03) | 15 μM |
| PARP2 | 44 nM(7.44 ± 0.12) | 1.6 μM | 10 μM |
| PARP3 | 8.8 μM | 34 μM | 50 μM |
| PARP4 | 6.0 μM | 10 μM | 11 μM |
| TNKS1 | 1.6 μM | 2.1 μM | 5.4 μM |
| TNKS2 | 370 nM(6.43 ± 0.13) | 5.7 μM | 10 μM |
| PARP6 | ≫10 μMa | >10 μMb | 7.7 μM |
| PARP7 | ≫10 μM | 3.8 μM | 83 nM(7.08 ± 0.06) |
| PARP10 | 2.9 μM | 25 nM(7.60 ± 0.03) | 7.8 nM(8.11 ± 0.12) |
| PARP11 | 9.4 μM | 470 nM(6.33 ± 0.13) | 240 nM(6.61 ± 0.07) |
| PARP12 | >10 μM | 4.4 μM | 160 nM(6.80 ± 0.002) |
| PARP14 | 6.7 μM | 650 nM(6.19 ± 0.03) | 300 nM(6.52 ± 0.03) |
| PARP15 | 2.0 μM | 260 nM(6.59 ± 0.11) | 56 nM(7.25 ± 0.01) |
| PARP16 | >10 μM | 5.2 μM | 3.4 μM |
| Activity in Cellular Context | |||
| PARP10 rescue EC50 | inactive | 500 nM(443–750 nM) | 150 nM(103–279 nM) |
| Pharmacokinetic Profile | |||
| water solubility μg/mL (log s) | 24.91 (−3.885) | 37.56 (−3.735) | 12.60 (−4.298) |
| GI Papp × 10–6 cm/s(RM %) | 0.019 (1.4) | 0.281 (1.8) | 0.144 (1.3) |
| BBB Papp × 10–6 cm/s(RM %)c | 0.164 (1.4) | 0.475 (5.3) | 0.143 (3.4) |
| metabolic stablity % | 95.05 (4.95) | 99.14 (0.86) | 99.11 (0.89) |
| stab in human plasma (h) | >24 | >24 | >24 |
| stab. in MeOH (h) | >24 | >24 | >24 |
| stab in PBS pH 7.4 (h) | >24 | >24 | >24 |
a
≫Denotes no inhibition at the reported concentration.
b
>Denotes less than 50% inhibition in the reported highest concentration.
c
Value for olaparib tested in parallel: 0.016 (3.0). RM %: retention membrane percentage.