NVP-AEW541

Reagent Authentication Certificate:

Chemical Probes Portal NVP-AEW541.pdf

Protein target name:

IGF1R

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

Up to 200 nM

Probe Availability

Cayman (NVP-AEW541 hydrochloride)

MedChem Express (475489-16-8)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:5465

Entrez gene ID:

3480

UNIPROT ID:

P08069

Target alias:

CD221, IGFIR, IGFR, JTK13

Probe Details

Chemical Probes Portal ID:

CPP101

Probe alias:

475489-16-8, AEW-541, AEW541, 475488-34-7, AVP-AEW541

PubChem CID:

11476171

ChEMBL ID:

CHEMBL3188172

SMILES string:

C1CN(C1)CC2CC(C2)N3C=C(C4=C3N=CN=C4N)C5=CC(=CC=C5)OCC6=CC=CC=C6

InChi Key:

AECDBHGVIIRMOI-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

150 nM

Potency assay:

in vitro kinase assay on isolated kinase domain

Off target activity

Potency (off target):

IC50

Off target protein and potency:

Ins-R 140 nMTEK 530 nMFLT1 600 nMFLT3 420 nM

Potency assay (off target):

NVP-AEW541 was at least 10-fold selective for IGF1R over all kinases tested except those listed.

In cell validation

On target activity in cells

Potency in cells:

IC50

86 nM

Potency assay (cells):

Inhibition of autophosphorylation; NVP-AEW541 also dose-dependently inhibited phosphorylation of IGF1R substrates in cells

Target engagement assay (cells):

Indirect: inhibition of autophosphorylation and protein substrate phosphorylation

Off target activity in cells

Potency in cells, off target:

IC50

Off target protein and potency (cells):

Ins-R 2.3 uM

Potency assay, off target (cells):

NVP-AEW541 is 27-fold selective for inhibition of IGF1R autophosphorylation > Ins-R autophosphorylation, and had negligible activity against several other tyrosine kinases.

In vivo validation

Organism:

athymic nude mice

Dose:

20-50 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Indirect: inhibition of protein substrate phosphorylation in xenograft tissue

Primary Reference

Reference (doi):

10.1016/S1535-6108(04)00051-0

Reference (PMID):

15050915

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This compound is a potent inhibitor of IGF-1R with cellular activity. Even though the compound has been screened against only a small number of other kinases, it shows some off-target activity, at least in biochemical assays. This compound is orally bioavailable and has been employed in in vivo experiments. It's selectivity profile has not been broadly defined.

Jun 12 2016 - 2:30pm

This probe is suggested to be selective ATP-competitive inhibitor of IGF-1R, and to the lesser extent IR. The original paper (Cancer Cell. 2004 Mar;5(3):231-9) reports a 150 nM IC50 for IGF-1R and 140 nM IC50 for IR in vitro. In cell based assays that monitor autophosphorylation of IGF-1R and IR, the compound is more selective for IGF-1R (IC50 86 nM for IGF-1R and 2300 nM for IR). Based on in vitro biochemical assays compound potently inhibit kinase TEK, FLT-1, and FLT-3. Since kinome-wide selectivity of the probe was not evaluated, it can potentially inhibit other kinases in cells. The second paper (Cancer Res. 2005 May 1;65(9):3868-76); however, shows the correlation between the sensitivity of Ewing's Sarcoma, osteosarcoma and rhabdomyosarcoma cells to NVP-AEW541. This suggests that the compound had a major effect in those cell lines due to the inhibition of IGF-1R. Users should always confirm that NVP-AEW541 does not inhibit AKT phosphorylation upon EGF stimulation and does not inhibit IR autophosphorylation, to confirm selectivity. The original paper reports the inhibition of IGF-1R phosphorylation in vivo; however, data to confirm selectivity at the doses used were not provided.

Jun 30 2016 - 4:06am

NVP-AEW541 is a potent inhibitor of IGF-1R and is useful for biochemical, cellular and in vivo studies. I recommend it for use with the caveat that its characterization is incomplete. It was reported prior to the availability of methods for the broad evaluation of kinase activity, and there is some degree of off-target activity even in the narrower characterization it has received.

Sep 12 2016 - 6:46pm

NVP-AEW541

Probe Availability

Probe Information

Target Details

CD221, IGFIR, IGFR, JTK13

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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NVP-AEW541

Probe Availability

Probe Information

Target Details

CD221, IGFIR, IGFR, JTK13

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?