SYK inhibitor | BI 1002494
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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.).
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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)
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
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
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
