BGJ-398

Reagent Authentication Certificate:

Chemical Probes Portal BGJ-398.pdf

Protein target name:

FGFR1, FGFR2, FGFR3, FGFR4

Recommended Concentration for use in cells:

Up to 100 nM

Probe Availability

MedChem Express (872511-34-7)

Cayman (872511-34-7)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Tyrosine Kinase

HUGO symbol:

FGFR1 FGFR2 FGFR3 FGFR4

Entrez gene ID:

2260 2263 2261 2264

Probe Details

Chemical Probes Portal ID:

CPP112

Probe alias:

NVP-BGJ398, 872511-34-7, BGJ398

PubChem CID:

53235510

ChEMBL ID:

CHEMBL1852688

SMILES string:

CCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl

InChi Key:

QADPYRIHXKWUSV-UHFFFAOYSA-N

PAINs evaluation:

Yes, but note that this is recognized as a PAIN by virtue of a p-aminotertiary aniline group and the PAINS moeity responsible is touted as an alphascreen-selective interence moeity, not a general promiscuity moiety

Physico-chemical properties

NMR:

1H NMR (600 MHz, DMSO-d6) δ 1.02 (t, J = 7.1 Hz, 3 H), 2.35 (q, J = 7.2 Hz, 2 H), 2.412.50 (m, 4 H), 3.033.12 (m, 4 H), 3.29 (s, 3 H), 3.93 (s, 6 H), 6.39 (s, 1 H), 6.89 (s, 1 H), 6.91 (d, J = 9.2 Hz, 2 H), 7.39 (d, J = 8.3 Hz, 2 H), 8.37 (s, 1 H), 9.44 (s, 1H), 12.05 (s, 1 H). 13CNMR (151MHz, DMSO-d6) δ 12.0, 31.7, 48.6 (2 C), 51.6, 52.4 (2 C), 56.7 (2 C), 89.8, 96.6, 112.6 (2 C), 115.8 (2 C), 122.0 (2 C), 134.5, 147.3, 152.8, 154.2 (3 C), 155.9, 159.2, 161.7

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

1 nM

Potency assay:

FGFR1 0.9 nM; FGFR2 1.4 nM; FGFR3 1.0 nM; FGFR4 60 nM

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

3TT0

Off target activity

Potency assay (off target):

BGJ-398 was tested against an in-house panel of 76 kinases

Selectivity against non-family targets:

BGJ-398 was tested against CYP450 enzymes 3A4, 2C9, 2C19, 2D6 and 1A2 all with IC50 > 10 uM

In cell validation

On target activity in cells

Potency in cells:

IC50

5 nM

Potency assay (cells):

ELISA-based detection of protein substrate phosphorylation in BaF3 cells

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation

In vivo validation

Organism:

Nude mice

Dose:

5 mg/kg

Route of delivery:

Intravenous

Other route of delivery:

Oral: 20 mg/kg

Plasma half life:

9.3 h (IV), 4.3 h (oral)

Systemic clearance:

3.3 L/h/kg (IV)

Cmax:

0.86 uM (IV), 0.42 uM (oral)

Tmax:

1 hr (oral)

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Indirect: inhibition of substrate phosphorylation in xenograft tissue

Primary Reference

Reference (doi):

10.1021/jm2006222

Reference (PMID):

21936542

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This probe has single-digit nM potency on FGFR1,2,3 in both in vitro biochemical and cell-based assays. It shows potency against only 76 other kinases assayed with most significant activity on FGFR4 (60 nM) and VEGFR2 (180 nM). Its selectivity against several related kinases remains unknown, however, (e.g. FLT1, CSFR, c-Kit, etc), which leads to some concern. Control of FGFR-driven tumor xenograft seen at doses 5 mg/kg - 30 mg/kg in multiple models. The preferred probe for FGFR4 is BLU9931 (Cancer Discovery, Hagel et al. 2015).

This compound is a pan FGFR inhibitor in the nM range with other kinases only being inhibited at high (triple digit) nM or low uM in cells. I think this probe is the best so far though, ideally, there would be separate probes for FGFR 1-4.

This probe is a potent and selective inhibitor of FGFR1/2/3 (though less potent against FGFR4). It acts as an adequate in vitro and in vivo inhibitor tool for these kinases.

BGJ-398

Probe Availability

Probe Information

Target Details

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

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BGJ-398

Probe Availability

Probe Information

Target Details

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?