Table 4. Summary of Properties of Notum Inhibitors LP-922056 (26), ABC99 (27), and ARUK3001185 (28).
| LP-922056 (26) | ABC99 (27) | ARUK3001185 (28) | |
|---|---|---|---|
| Physicochemical Properties | |||
| mol wt | 300 | 456 | 281 |
| clogP | 3.1 | 4.3 | 3.9 |
| logD7.4 | nda | nd | 1.3 |
| Notum Inhibition | |||
| OPTS, IC50 (nM) | 1.1 | 170b,c | 6.5 |
| gel-based ABPP, IC50 (nM) | nd | 13 | nd |
| TCF-LEF, EC50 (nM) | 23 | 89 | 110 |
| Selectivity | |||
| serine hydrolases (number screened) | nd | yes (64) | yes (49) |
| drug targets (number screened) | nd | nd | yes (47) |
| kinases (number screened) | nd | nd | yes (485) |
| Mouse Pharmacokinetics (1 mg/kg iv and 10 mg/kg po) | |||
| half-life (t1/2, h) | 8.3 | nd | 2.4 |
| oral bioavailability (Fo, %) | 65 | nd | 68 |
| exposure (Cmax) (po) | 129 μM | nd | 2300 ng/mLd |
| exposure (AUC∞) (po) | 1533 μM*h | nd | 10 800 (ng·h)/mLd |
| mouse plasma protein binding (mPPB) (fu, %) | 0.1 | nd | 4.2 |
| brain/plasma ratio (Kp) (po) | <0.01 | nde | 1.08 |
| Mouse In Vivo Studies | |||
| route of administration and dosing regime | 3, 10, 30 mg/kg, po, 25 days | 10 mg/kg, ip, 7 days | 2 × 30 mg/kg bid, po, 30 days |
| Rat In Vivo Studies | |||
| route of administration and dosing regime | 30 mg/kg, po, 126 days | nd | nd |
| refs | (95, 98, 116) | (102, 106, 118) | (125−127) |
a
nd, not determined or not disclosed.
b
Notum IC50 data presented for comparison in a common assay format.
c
As a covalent inhibitor, the IC50 value will be time dependent.
d
For ease of comparison of Cmax and AUC∞ data, 2300 ng/mL is equivalent to 8.2 μM and 10 800 (ng·h)/mL to 38 μM*h, respectively.
e
ABC99 is reported to be brain penetrant in mouse; see, ref (106).