NVP-CLR457
NVP-CLR457 (compound 40) is an orally active, potent and balanced pan-class I PI3K inhibitor. NVP-CLR457 shows a clear dose-dependent PK/PD/efficacy relationship. NVP-CLR457 has antitumor activity.
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- CAS No.: 1453082-52-4
- Formule: C18H20F3N7O4
- Masse moléculaire:455.39
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
IC50 & Target
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PI3Kα 12 ± 1.5 nM (IC50) |
PI3Kβ 8.3 ± 1.0 nM (IC50) |
PI3Kδ 8.3 ± 2.0 nM (IC50) |
PI3Kγ 230 ± 31 nM (IC50) |
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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:U87MG cells[1]
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Concentration:0, 1. 4, 16, 63, 250, 1000 nM
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Incubation Time:24 h
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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.
In Vivo
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 |
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 |
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 |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague Dawley rats (male)[1]
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Dosage:1 mg/kg (IV), 3 mg/kg (PO)
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Administration:IV or PO, once (Pharmacokinetic Analysis)
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Result:Showed high level of oral exposure and bioavailability.
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Animal Model:Female OF1 mice, male beagle dogs[1]
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Dosage:3 mg/kg (IV) and 10 mg/kg (PO) for mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for dogs
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Administration:IV or PO, once (Pharmacokinetic Analysis)
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Result:Showed low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability.
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Animal Model:Male Sprague Dawley rats, male beagle dogs[1]
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Dosage:0.3, 3, 30, 100 mg/kg
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Administration:PO, once (Pharmacokinetic Analysis)
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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.
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Animal Model:Female athymic nude mice (bearing xenotransplanted Rat1-myr-p110α tumors)[1]
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Dosage:3, 10, and 20 mg/kg
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Administration:PO, daily for 8 days
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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%).
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Animal Model:Mice bearing xenograft HBRX2524 human primary breast tumor[1] Dosage: 40 mg/kg
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Dosage:40 mg/kg
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Administration:PO, daily for 15 days
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Result:Inhibited the tumor growth throughout the study, and showed a significant level of regression the end of the 15 day treatment period.
Chemical Information
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CAS No. 1453082-52-4
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Masse moléculaire 455.39
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Formule C18H20F3N7O4
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SMILES
NC1=NC(C(F)(F)F)=C(C2=NC(N3CCOCC3)=NC(N4[C@H]([C@H](OC4=O)C)CO)=C2)C=N1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
NVP-CLR457 Related Classifications
HY-146260 Related Classifications
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