2. PI3K/Akt/mTOR
  3. PI3K
  4. 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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NVP-CLR457 Chemical Structure

NVP-CLR457 Chemical Structure

CAS No. : 1453082-52-4

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NVP-CLR457 Related Antibodies

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PI3Kα PI3Kβ PI3Kγ PI3Kδ PI3KC2α PI3KC2β PI3KC2γ Vps34 PI3K PI3KC3 p120γ

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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].

IC50 & 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

NVP-CLR457 Related Antibodies

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 (%) 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

MedChemExpress (MCE) 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.
Molecular Weight

455.39

Formula

C18H20F3N7O4
CAS No.
SMILES

NC1=NC(C(F)(F)F)=C(C2=NC(N3CCOCC3)=NC(N4[C@H]([C@H](OC4=O)C)CO)=C2)C=N1
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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NVP-CLR457 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

NVP-CLR4571453082-52-4PI3KPhosphoinositide 3-kinaseU87MG cellsHematological cell linesRat1-myr-p110α tumorsHBRX2524 human primary breast tumorOrally activeAntitumor activityInhibitorinhibitorinhibit

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