FGFR3-IN-10s

FGFR3-IN-10s : Covalent Inhibitor of FGFR3

Structure

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Information

FGFR3 (Mutant:WT, V555M)

Covalent Inhibitor

up to 500 nM

In Vitro Validations

Uniprot ID: P22607

Target Class: Kinase

Target SubClass: Tyr kinase

Potency: IC50

Potency Value: 6.8 nM

Potency Assay: Biochemical Assay using WT recombinant FGFR3

PDB ID for probe-target interaction (3D structure): 9VM9

Target aliases:

Fibroblast growth factor receptor 3, JTK4, FGFR3, ...

DOI Reference: 10.1021/acs.jmedchem.5c02552

Uniprot ID: P22607

Target Class: Kinase

Target SubClass: Tyr kinase

Potency: IC50

Potency Value: 19.2 nM

Potency Assay: Biochemical Assay using recombinant FGFR3 V555M mutant

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

Target aliases:

Fibroblast growth factor receptor 3, JTK4, FGFR3, ...

DOI Reference: 10.1021/acs.jmedchem.5c02552

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): Compound 10s displayed promising FGFR3 selectivity in the cellular assays with an RT112/84 IC50 value of 9.2 nM, being 16.9, 3.2 and 48.6-fold selective over DMS-114, MFE-296 and MDA-MB-453 cells, respectively.

Potency assay (off target): Compound 10s demonstrated improved selectivity over FGFR1/2 (43.5/5.3-fold)

Off Target: TNK1

Potency end-point : IC50 16.9 nM

Potency assay (off target): Kinase profiling of cpd 10s at a concentration of 0.5 μM was conducted against a panel of 330 wild-type kinases using the ICE Bioscience screening platform.

Probe Selectivity in Vitro:

Results demonstrated that cpd 10s displayed extraordinary kinome selectivity with S(1) and S(10) selectivity scores of 0.006 and 0.012, respectively. Potential “off-target” kinase hits were Thirty-eight Negative Kinase 1 (TNK1) and the homologous FGFR1/2/4 family members. Compound 10s was determined by Z′-Lyte assay to be a relative potent inhibitor of TNK1 (IC50 = 16.9 nM), while being less potent against FGFR1, FGFR2 and FGFR4 with IC50 values of 296.2, 35.7, and 414.5 nM, respectively.

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