ATP-competitive inhibitor of PDGFRB



Protein target names: PDGFRB

Mechanism of action: ATP-competitive inhibitor

Primary References:

In Vitro Validations

Uniprot ID: P09619
Target Class: Protein kinase
Target SubClass: TK
Potency: IC50
Potency Value: 1 nM
Potency Assay: PDGFRalpha IC50 = 10 nM, enzyme assays with GST-tagged intracellular domains
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Platelet-derived growth factor receptor beta, PDGF ...

In Cell Validations

In Vivo Data

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP 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).

(last updated: 18 Aug 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

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.

(last updated: 2 Nov 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 15 Jun 2017 )