1453082-52-4
1453082-52-4 structure
- Name: NVP-CLR457
- Chemical Name: NVP-CLR457
- CAS Number: 1453082-52-4
- Molecular Formula: C18H20F3N7O4
- Molecular Weight: 455.39
- Catalog: Signaling Pathways PI3K/Akt/mTOR PI3K
- Create Date: 2022-07-19 19:11:00
- Modify Date: 2024-01-14 22:38:04
-
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[1].
| Name | NVP-CLR457 |
|---|
| Description | 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[1]. |
|---|---|
| Related Catalog | |
| Target |
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]. 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. |
| 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 (%) 37NVP-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 ± 0.6NVP-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. |
| References |
| Molecular Formula | C18H20F3N7O4 |
|---|---|
| Molecular Weight | 455.39 |