CP-673451

ATP-competitive inhibitor of PDGFRB

Structure

Information

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

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

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.

(last updated: 2 Nov 2016 )

SERP Ratings

Comments:

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: 4 Nov 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

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 )