BLU9931

Covalent inhibitor of FGFR4

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(2 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

FGFR4

Covalent inhibitor

Probe Availability:

In Vitro Validations

Uniprot ID: P22455

Target Class: Protein kinase

Target SubClass: TK

Potency: Kinact/KI

Potency Value: 0.6 X 10^5/(mol/L) s

Potency Assay: Omnia assay technology (Life Technologies); Incubation of recombinant FGFR4 with BLU9931 led to covalent modification of the receptor at Cys552, confirmed by mass shift and proteomics. In enzyme activity assays FGFR4 IC50=3 nM.

PDB ID for probe-target interaction (3D structure): 4XCU

Target aliases:

Fibroblast growth factor receptor 4, TKF, JTK2, FG ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 FGFR1: 591 nM, FGFR2: 493 nM, FGFR3: 150 nM

Potency assay (off target): In kinome-wide selectivity panel containing 456 kinases (Kinomescan, DiscoveRx), BLU9931 bound significantly to only FGFR4 (KD=6 nM) and CSFR1 (KD=2,716 nM) at 3 uM, yielding a selectivity score S(10)=0.005.

Potency assay, off target (cells): In FGFR1-driven cells (DMS114), BLU9931 had minimal activity.

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 15 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Overall, the selectivity (and limits thereof) has been appropriately validated. Direct evidence for cellular or in vivo target engagement is lacking. In addition, it should also be noted than IC₅₀ values for irreversible inhibitors are time-dependent.

(last updated: 28 Mar 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

This molecule represents the most selective FGFR4 inhibitor available. KINOMEscan methodology indicated that the only other kinase outside the FGFR family that is potentially inhibited is CSF1R (KD is significantly weaker at 2,716 nM vs. 6 nM for FGFR4). The compound demonstrates prolonged inhibitory activity in cell lines after removal of compound (~8 hrs), consistent with its covalent mode of action and the rate of resynthesis of EGFR4 protein. Addition of glutathione to enzyme activity assays produces a negligible IC₅₀ shift indicating that the compound does not elicit general thiol reactivity. Impressive efficacy was demonstrated in vivo in xenograft models of HCC after oral administration at the well tolerated 100-300 mg/kg, twice daily doses.

(last updated: 28 Mar 2017 )