| efficacy |
|
|
| TNKS1 (IC50, nM (pIC50 ±
SEM))a
|
127 (6.90 ± 0.05) |
13 (7.90 ± 0.054) |
| TNKS2
(IC50, nM (pIC50 ±
SEM))a
|
14 (7.85 ± 0.04) |
2.0 (8.71 ± 0.069) |
| HEK293
reporter assay (IC50, nM (pIC50 ± SEM)) |
19 (7.75 ± 0.067) |
0.63 (9.22 ± 0.037) |
| COLO 320DM/RKO
cells (GI50, nM) |
650/>10 000 |
10/>10 000 |
| ADME |
|
|
| kinetic solubility PBS pH = 7 (μM) |
>80 |
31 |
| Caco-2
A–B: Papp (10–6 cm/s) |
39.5 |
40.5 |
| Caco-2 efflux ratio |
0.61 |
0.64 |
| microsomal
stability human/mouse/dog CLint (μL/min/mg protein) |
<5/27/nd |
18/22/3.8 |
| mouse plasma stability t1/2 (min) |
>120 |
>120 |
| mouse PPB (%) |
93.92 |
98.58 |
| off-target |
|
|
| PARPsb PARP1/2/3/4/10/12/14/15
(IC50, μM) |
>10 |
>10 |
| hERG inhibition
(IC50, μM) |
>25 |
>25 |
| Ames test |
nongenotoxic |
nongenotoxic |
| CYP3A4 inhibition (IC50, μM) |
>25 |
>25 |
| CYP induction (human PXR) |
nd |
nonactivatorbc
|
| Cerep Safety panel 44 targets@10 μM (inhibition) |
clean, (A2A, 53%) |
clean, (all <50%) |
| mouse pharmacokinetics |
|
|
| PO PK
mouse t1/2 (h) |
0.67 |
1.5 |
| PO PK mouse Cmax (ng/mL) |
3202 |
1967 |
| PO PK mouse CL (L/h/kg) |
2.09 |
0.99 |
| PO PK mouse Vd (L/kg) |
2.03 |
2.15 |
| PO PK mouse AUC 0 → t (ng/mL) |
2384 |
4945 |
| calculated propertiesd
|
|
|
| MW (g/mol) |
458.5 |
509.6 |
| clog P
|
3.1 |
3.4 |
| tPSA |
95 |
108 |
