PRT062607

Reagent Authentication Certificate:

Chemical Probes Portal P505-15.pdf

Protein target name:

SYK

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

100 nM - 2 uM

Probe Availability

MedChem Express (1370261-96-3)

Cayman (1370261-96-3)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:11491

Entrez gene ID:

6850

UNIPROT ID:

P43405

Probe Details

Chemical Probes Portal ID:

CPP90

Probe alias:

P505-15, PRT-062607, BIIB057

PubChem CID:

44462758

ChEMBL ID:

CHEMBL2177736

SMILES string:

C1CC[C@H]([C@H](C1)N)NC2=NC=C(C(=N2)NC3=CC=CC(=C3)N4N=CC=N4)C(=O)N

InChi Key:

TXGKRVFSSHPBAJ-JKSUJKDBSA-N

Orthogonal probe:

Entospletinib

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

2.1 nM

Potency assay:

Radiometric assay; in a FRET-based assay, IC50 = 6 nM

Off target activity

Potency (off target):

IC50

Off target protein and potency:

FGR 81 nMMLK1 88 nMYES 123 nMFLT3 139 nMPAK5 166 nMLYN 192 nMSRC 244 nMLCK 249 nMPYK2 108 nM

Potency assay (off target):

Radiometric assay. At 50 nM, P505-15 was selective for SYK over 270 other kinases; at 300 nM, it inhibited 8 additional kinases >80%.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.16-0.4 uM

Potency assay (cells):

Inhibition of protein substrate phosphorylation in B cells

Target engagement assay (cells):

Indirect: inhibition of substrate phosphorylation in B cells

Off target activity in cells

Potency assay, off target (cells):

No activity was detected against LYN substrates in B cells.

In vivo validation

Organism:

mice

Dose:

30 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

B cells

Target engagement assay:

Indirect: inhibition of SYK substrate phosphorylation but not LYN substrate phosphorylation

Primary Reference

Reference (doi):

10.1124/jpet.111.188441

Reference (PMID):

22040680

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

I recommend this compound as "best available" for use in cells; it is potent and cell active and almost meets a high bar for selectivity when broadly profiled. I also recommend this compound as "best available" for use in mice and rats. The original publication shows the PK data and use of the compound in in vivo models.

Jun 16 2016 - 3:54pm

P505-15 is a small molecule, and a potent and selective inhibitor of SYK. It inhibits SYK and suppresses BCR signaling in SUDHL4 cells and inhibits SYK-dependent signaling in human whole blood. P505-15 reversibly inhibited SYK in mice after oral dosing.

Sep 12 2016 - 6:38pm

Highly selective inhibitor of Spleen Tyrosine Kinase (SYK). Exhibits ~80-fold selectivity for SYK over the next target. Shows 1 nM potency against SYK, with substantially lower potency towards the three related kinases PTK2 (415 nM), PTK2B (108 nM), and ZAP70 (1050 nM). Potently inhibits SYK activity in cells without interfering with its activation. Potently and selectively inhibits SYK-mediated signaling in human whole blood. Orally available, with dose-dependent anti-inflammatory activity in rodent models at doses that specifically suppress SYK activity.

May 1 2017 - 5:14pm

PRT062607

Probe Availability

Probe Information

Target Details

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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PRT062607

Probe Availability

Probe Information

Target Details

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?