体外研究
(In Vitro) | NVP-CLR457 (compound 40) shows the mTOR activity, with an IC50of 2474 ± 722 nM, and inhibits RPS6 phosphorylation with an IC50of 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].
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 IC50and IC90values of 100 and 507 nM determined for the inhibition of S473P-Akt, and had no significant change in the readouts of mTOR activity. |
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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 |
| 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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