CP-673451

Protein target name:

PDGFRbeta

Mechanism of action:

ATP-competitive inhibitor

Probe Availability

MedChem Express (343787-29-1)

Tocris (343787-29-1)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Tyrosine kinase

HUGO symbol:

PDGFRB

Entrez gene ID:

5159

Target alias:

CD140B, IBGC4, IMF1, JTK12, KOGS, PDGFR, PDGFR-1, PDGFR1, PENTT

Probe Details

Chemical Probes Portal ID:

CPP127

Probe alias:

CP 673451

PubChem CID:

10158940

SMILES string:

COCCOC1=CC2=C(C=C1)N(C=N2)C3=NC4=C(C=CC=C4N5CCC(CC5)N)C=C3

InChi Key:

DEEOXSOLTLIWMG-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

1 nM

Potency assay:

PDGFRalpha IC50 = 10 nM, enzyme assays with GST-tagged intracellular domains

Off target activity

Potency (off target):

IC50

Off target protein and potency:

KIT 252 nMVEGFR1 450 nMVEGFR2 450 nM

Potency assay (off target):

CP673451 was tested at 100 nM in Kinase Profiler assay in vitro, and was 1,000-10,000-fold selective for PDGFRs over other receptor tyrosine kinases and >200-fold selective for other kinases.

In cell validation

On target activity in cells

Potency in cells:

IC50

1 nM

Potency assay (cells):

PDGFRalpha IC50 = 14 nM in autophosphorylation and protein substrate phosphorylation assays

Target engagement assay (cells):

Indirect: inhibition of autophosphorylation and substrate phosphorylation

Off target activity in cells

Potency in cells, off target:

IC50

Off target protein and potency (cells):

KIT 1 uM

Potency assay, off target (cells):

Inhibition of substrate phosphorylation

In vivo validation

Organism:

CD1 nu/nu mice

Dose:

10-100 mg/kg

Route of delivery:

Oral

Plasma half life:

2-3 hr

Cmax:

5.5 ng/mL

Tmax:

1-2 hr

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Ex vivo ELISA to assess inhibition of substrate phosphorylation

Primary Reference

Reference (doi):

Cancer Res

Reference (PMID):

15705896

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Chemical Neighbourhood for QSAR: 18 molecules similar (>0.80) to CP-673451 with in vitro affinities for PDGFRbeta were found in public repositories (e.g., ChEMBL).

On-Target links to toxicities: PDGFRbeta has been associated with hemotoxicities (e.g., bleeding, hemorrhage, cytopenia).

The limited public information on this compound does not provide high confidence in its utility as a probe to evaluate PDGFR biology. The probe has been reported to enzyme potency in 1-10 nM range with cell activity below 10 nM. The good translation from enzyme to cell readout considering the Km for PDGFRb is reported to be 4 uM is unexpected. The selectivity using 100 nM concentration of compound for a very limited number of kinases is acceptable. The chemotype has been reported to hit many kinases, and the kinome-wide selectivity must be profiled if this tool is being used to discover novel biology to ensure that it is not originating from an unknown off-target. Crenolanib, a very similar compound, has potent activity on FLT3 and mutant cKIT, neither of which have been evaluated for this compound. In general, the compound could be used in cell-based assays at concentration below 100 nM, which would be around the IC90 for the target based on reported data.

The published data for CP-673451 indicates that it is a highly potent and selective inhibitor of PDGFR relative to other anti-antiogenic receptors, including VEGFR, TIE-2 and c-KIT, though the panel of kinases that have been measured is limited (<50). The compound has excellent in vivo activity in terms of anti-tumor growth and inhibition of PDGFR-beta phosphorylation, and it was demonstrated to have ex-vivo pharmacodynamic effects in a sponge angiogenesis model. Because CP-673451 is nonselective with regards to PDGF-alpha (~10-fold in vitro and in cells), this compound cannot discern what contribution to in vivo antitumor efficacy is due to PDGFR-beta versus alpha, nor if other kinases that were not tested contribute to the in vivo profile. A full assessment of the utility of the probe still requires broad kinase profiling (e.g., against the DiscoverX panel of >400 kinases). Appropriate application will require users to tease apart the contributions of PDGFR-beta and alpha. Nonetheless, the suitable properties of CP-673451 and its potent in vivo pharmacodynamic activity with excellent tolerability make it a useful probe for interrogating the impact of PDGF-beta inhibition.

This probe has been extensively characterize in vivo and has demonstrated on-target pharmacodynamic activity in various xenograft models at doses that were well tolerated. CP-673451 shows good selectivity against a panel receptor tyrosine kinases, as well as broad kinase selectivity against a set of representative kinases. The fact that the probe lacks selectivity against PDGFR-alpha (i.e., is within 10-fold potency in vivo and in cells relative to PDGFR-beta) and has not been profiled against a broader set of kinases makes it difficult to ascribe in vivo efficacy exclusively to PDGFR-beta. Nonetheless, its potent biochemical and cellular activity against PDGFR-beta and the fact that it covers the target well in vivo make it a fairly useful probe to study the importance of PDGFR-beta in an in vivo setting. To fully rule out off target activities in vivo, a more complete set of kinase data would be desirable.

CP-673451

Probe Availability

Probe Information

Target Details

CD140B, IBGC4, IMF1, JTK12, KOGS, PDGFR, PDGFR-1, PDGFR1, PENTT

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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CP-673451

Probe Availability

Probe Information

Target Details

CD140B, IBGC4, IMF1, JTK12, KOGS, PDGFR, PDGFR-1, PDGFR1, PENTT

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?