SGX-523

Reagent Authentication Certificate:

Chemical Probes Portal SGX-523.pdf

Protein target name:

MET

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

1 nM - 1 uM

Probe Availability

Tocris (1022150-57-7)

Cayman (1022150-57-7)

MedChem Express (1022150-57-7)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Tyrosine Kinase

HUGO symbol:

MET

Entrez gene ID:

4233

Target alias:

AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

Chemical Probes Portal ID:

CPP81

PubChem CID:

24779724

ChEMBL ID:

CHEMBL1236107

SMILES string:

CN1C=C(C=N1)C2=NN3C(=NN=C3SC4=CC5=C(C=C4)N=CC=C5)C=C2

InChi Key:

BCZUAADEACICHN-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H NMR (500 MHz, DMSO–d6): δ 8.89 p.p.m. (dd, J= 1.5, 4.0 Hz, 1H), 8.46 (d, J= 9.5 Hz, 1H), 8.45 (s, 1H), 8.35 (dd, J= 1.5, 8.0 Hz, 1H), 8.15 (d, J= 2.5 Hz, 1H), 8.01 (s, 1H), 7.99 (d, J= 8.5 Hz, 1H,), 7.79 (d, J= 9.5 Hz, 1H), 7.75 (dd, J= 2.5, 8.5 Hz, 1H), 7.55 (dd, J= 4.0, 8.0 Hz, 1H), 3.89 (s, 3H); analysis (% calcd, % found for C18H13N7S): C (60.15, 59.81), H (3.65, 3.88), N (27.28, 27.38), S (8.92, 8.81)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

2.7 nM

Potency assay:

In vitro kinase assay IC50 = 4 nM

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

3DKF

Off target activity

Potency (off target):

IC50

Off target protein and potency:

RON ~10 uM

Potency assay (off target):

At 1,000 nM, SGX-523 did not inhibit any of 213 kinases >36%, making it at least 1,000-fold selective for wild type MET.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.012 uM

Potency assay (cells):

In A549 cells, SGX-523 inhibited MET autophosphorylation; IC50 = 0.04 uM in GTL16 cells. SGX-523 dose-dependently inhibited phosphorylation of MET substrates.

Target engagement assay (cells):

Indirect: inhibition of autophosphorylation and phosphorylation of protein substrates

Off target activity in cells

Potency assay, off target (cells):

SGX-523 did not effect phosphorylation of substrates of RON or 8 other kinases.

Primary Reference

Reference (doi):

1158/1535-7163.MCT-09-0477

Reference (PMID):

19934279

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

SGX523 potently inhibited MET with an IC50 of 4 nM and is >250-fold selective versus 213 other protein kinases, representing approximately half of all catalytically competent human protein kinases and three quarters of all human protein tyrosine kinases. Cellular activity against MET-dependent cell lines was reported as EC50 = 5-113 nM. In vivo target engagement and tumor-growth inhibition were reported following oral administration to mice (10-100 mg/kg dosed twice daily).

In vitro potency data against MET are for the kinase domain only and not the full-length enzyme.

Selectivity and cellular activity are appropriate for use of this compound as a probe.

From a chemists point of view, this compound is a good probe.

This is an excellent probe molecule. It was highlighted in the famous Nature Biotechnology kinase inhibitor article (Nature Biotechnology 2011, 29, 1046–1051) as one of the most selective kinase inhibitors known. It shows both pharmacodynamic and functional cellular potency in line with its biochemical data as well as robust dose-responsive tumor-growth inhibitory effects in relevant xenograft mouse models. In terms of pre-clinical species, there are no limitations using this compounds in rodents and dog.

SGX-523

Probe Availability

Probe Information

Target Details

AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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SGX-523

Probe Availability

Probe Information

Target Details

AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?