SYK inhibitor | BI 1002494

Target protein: 
SYK
Probe Name: 
BI 1002494
MOLECULAR WEIGHT [DA]: 
423.5
In stock: 
7246

Chemical structure

2D Structure of BI 1002494

Highlights

BI 1002494 is a potent inhibitor of SYK with an IC50 of 0.8 nM and inhibits in human whole blood the DNP/BSA (dinitroprusside / bovine serum albumine) induced expression of CD63 in basophils with an average IC50 of 115 nM (N=263) as well as in human B cells the goat anti-human IgD induced secretion of CD69 with an IC50 of 810 nM (N=36). In addition to its excellent target inhibition, its high solubility and metabolic stability makes it a suitable tool for in vivo mouse and rat studies. For instance, it showed 90% reduction of BAL (bronchoalveolar lavage) eosinophils in a rat OVA model at 30 mg/kg (b.i.d.). No adverse events were observed in a 13-week mouse toxicology study up to 100 mg/kg (b.i.d.).

3D structure of BI 1002494

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Target information

SYK propagates signal transduction for a number of immunoreceptor tyrosine-based activation motif–dependent proinflammatory pathways, including Fc receptor, B-cell receptor (BCR), and integrin signaling.

BI 1002494 in complex with SYK (X-ray structure solved at Boehringer Ingelheim)

BI 1002494 in complex with SYK (X-ray structure solved at Boehringer Ingelheim)

In vitro Activity

BI 1002494 inhibits SYK with an IC50 of 0.8 nM

Probe name BI 1002494
MW [Da] 423.46
SYK (IC50) [nM] 0.8
CD63 (EC50) [nM] human whole blood 115*
CD69 (EC50) [nM] human whole blood 810**

*N=263

**N=36

In vitro DMPK parameters

Probe name BI 1002494

Solubility @ pH 7.4 [µg/ml]

500
CACO permeability @ pH 7.4 [*10-6 cm/s] 30

CACO efflux ratio

2.8
Mouse / Rat hepatocyte clearance [%QH] n.d. 51
Plasma protein binding mouse / rat [%] 93 95

In vivo DMPK parameters

In vivo DMPK parameters table

BI 1002494 Mouse Rat
CL [%QH] 58 41
MRT [h] 0.4 0.9
Vss [L/kg] 0.8 1.5
F [%] 58 41

In vivo pharmacology

BI 1002494 showed 90% reduction of BAL (bronchoalveolar lavage) eosinophils in rat OVA (ovalbumin) model at 30 mg/kg. Rat passive anaphylaxis pulmonary model IC50,unbound = 50 nM. 1

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
423.5

BI-2492

BI-2492

With BI-2492 a structurally very similar molecule (diastereoisomer) with an SYK IC50 = 625 nM (780-fold less potent than BI 1002494) is offered which can be used as a negative control.

Selectivity

Invitrogen® 23/239 kinases hit > 50% INH @ 1 µM

Cerep®: 3/56 targets > 50% INH @ 10 µM (M1 (h): 70%, A1 (h): 63%, A2A (h): 59%.)1

  BI 1002494
Cerep® Yes
Eurofins-Panlabs® No
Invitrogen® Yes

DiscoverX®

No

Dundee

No

Selectivity data and assay condition can be downloaded free of charge from this site. 1

Download selectivity data: 

Co-crystal structure of the BI probe compound and the target protein

No Xray co-crystal structure available

reference molecules

fostamatinib, entospletenib

Summary

BI 1002494 is due to its high potency, good physicochemical properties, suitable selectivity profile and low toxicity an excellent tool to explore SYK functions in vitro and in vivo.

Supplementary data

References

  1. The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction

    van Eeuwijk J.M., Stegner D., Lamb D.J., Kraft P., Beck S., Thielmann I., Kiefer F., Walzog B., Stoll G., Nieswandt B.

    Arterioscler Thromb Vasc Biol 2016;36:1247-1253.