体外研究
(In Vitro) |
NVP-CLR457 (compound 40) shows the mTOR activity, with an IC50 of 2474 ± 722 nM, and inhibits RPS6 phosphorylation with an IC50 of 1633 ± 54 nM[1].
NVP-CLR457 has no impact on the DDR response at concentrations of 1 and 5 μM[1].
NVP-CLR457 has no effect on the rate of microtubule polymerization[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Western Blot Analysis
| Cell Line: |
U87MG cells[1] |
| Concentration: |
0, 1. 4, 16, 63, 250, 1000 nM |
| Incubation Time: |
24 h |
| Result: |
Inhibited the readouts of class I PI3K activity in a dose-dependent manner, with IC50 and IC90 values of 100 and 507 nM determined for the inhibition of S473P-Akt, and had no significant change in the readouts of mTOR activity. |
|
体内研究
(In Vivo) |
NVP-CLR457 (compound 40) (athymic nude mice bearing xenotransplanted Rat1-myr-p110α tumors, 3-20 mg/kg, PO, daily for 8 days) shows a dose-dependent inhibition of tumor growth[1].
NVP-CLR457 (Mice bearing xenograft HBRX2524 human primary breast tumor, 40 mg/kg, PO, daily for 15 days) inhibits the tumor growth throughout the study[1].
NVP-CLR457 (male Sprague-Dawley rats, 1.0 mg/kg, IV; 3.0 mg/kg, PO; once) shows high level of oral exposure and bioavailability[1].
Pharmacokinetic Parameters of NVP-CLR457 in male Sprague-Dawley rats[1].
| compound |
40 |
| CL (mL/min/kg) |
22 ± 6 |
| Vss (L/kg) |
4.4 ± 0.2 |
| t1/2 (h) |
3.3 ± 0.2 |
| AUC iv (nM*h) |
1770 ± 443 |
| oral F (%) |
97 ± 20 |
| HDM FA (%) |
37 |
NVP-CLR457 (3 mg/kg (IV) and 10 mg/kg (PO) for female OF1 mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for male beagle dogs, once) shows low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability[1].
Pharmacokinetic Parameters of NVP-CLR457 in female OF1 mice and male beagle dogs[1].
| species |
mouse |
dog |
| PPB (%) |
76 |
71 |
| CL (mL/min/kg) |
10 |
3 ± 0 |
| Vss (L/kg) |
2 |
1.5 ± 0.2 |
| t1/2 (h) |
2 |
11 ± 3 |
| AUC iv (nM*h) |
3580 |
11213 ± 1169 |
| AUC po (nM*h) |
1738 |
11034 ± 1531 |
| oral F (%) |
49 |
98 ± 14 |
| Cmax (nM) |
422 |
1121 ± 128 |
| Tmax (h) |
0.5 |
1.3 ± 0.6 |
NVP-CLR457 (0.3-100 mg/kg, PO, once) leads to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values[1].
Pharmacokinetic Parameters of NVP-CLR457 in male Sprague Dawley rats, male beagle dogs[1].
| species |
rat |
|
|
dog |
|
| dose (mg/kg) |
3 |
30 |
100 |
0.3 |
3 |
| AUC (nM*h) |
1709 ± 362 |
913 ± 251 |
784 ± 342 |
12,970 ± 1828 |
11,213 ± 1169 |
| Cmax (nM) |
213 ± 61 |
41 ± 6 |
22 ± 4 |
1121 ± 128 |
309 ± 40 |
| Tmax (h) |
0.5-2 |
4–24 |
24 |
1-2 |
2-24 |
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: |
Sprague Dawley rats (male)[1] |
| Dosage: |
1 mg/kg (IV), 3 mg/kg (PO) |
| Administration: |
IV or PO, once (Pharmacokinetic Analysis) |
| Result: |
Showed high level of oral exposure and bioavailability. |
| Animal Model: |
Female OF1 mice, male beagle dogs[1] |
| Dosage: |
3 mg/kg (IV) and 10 mg/kg (PO) for mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for dogs |
| Administration: |
IV or PO, once (Pharmacokinetic Analysis) |
| Result: |
Showed low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability. |
| Animal Model: |
Male Sprague Dawley rats, male beagle dogs[1] |
| Dosage: |
0.3, 3, 30, 100 mg/kg |
| Administration: |
PO, once (Pharmacokinetic Analysis) |
| Result: |
Led to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values when it formulated as a suspension of the crystalline material. |
| Animal Model: |
Female athymic nude mice (bearing xenotransplanted Rat1-myr-p110α tumors)[1] |
| Dosage: |
3, 10, and 20 mg/kg |
| Administration: |
PO, daily for 8 days |
| Result: |
Observed dose-dependent exposure and PD responses, and showed a dose-dependent inhibition of tumor growth. The 3 mg/kg dose achieved 80% S473P-Akt inhibition only at the 1 h time point; the 10 mg/kg dose at the 1 and 4 h time points; and the 20 mg/kg at the 1, 4, and 10 h time points, with a high level of inhibition remaining at the 14 h time point (76%). |
| Animal Model: |
Mice bearing xenograft HBRX2524 human primary breast tumor[1] Dosage: 40 mg/kg |
| Dosage: |
40 mg/kg |
| Administration: |
PO, daily for 15 days |
| Result: |
Inhibited the tumor growth throughout the study, and showed a significant level of regression the end of the 15 day treatment period. |
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