AZD1332

Protein target name:

NTRK1, NTRK2

Mechanism of action:

Inhibitor, ATP competitive

Recommended Concentration for use in cells:

50-100 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:8031 HGNC:8032

Entrez gene ID:

4914 4915

UNIPROT ID:

P04629 Q16620

Target alias:

MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA, GP145-TrkB, TRKB, trk-B

Probe Details

Chemical Probes Portal ID:

CPP1232

Probe alias:

Kinome_3819, AZ-23, cpd 10z, V4Z

PubChem CID:

49831044

ChEMBL ID:

CHEMBL2007421

SMILES string:

CC(OC1=NNC(NC2=NC(N[C@H](C3=NC=C(F)C=C3)C)=NC=C2Cl)=C1)C

InChi Key:

LBVKEEFIPBQIMD-UHFFFAOYSA-N

Physico-chemical properties

Solubility - concentration:

100 uM

NMR:

1H NMR (300 MHz, CDCl3) δ ppm 8.45 (s, 1H), 7.90 (s, 1H), 7,35 (m, 2H), 6.30 (br s, 1H), 5.40 (s, 1H), 5.15 (m, 1H), 4.80 (m, 1H), 1.60 (m, 3H), 1.35 (m, 6H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

2 nM TRKA, 8 nM TRKB

Potency assay:

AlphaScreen and HTRF phosphorylation assay

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

4AOJ

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

FGFR1 24 nM

Probe Selectivity in Vitro:

In vitro selectivity profiling across a broad panel of 177 kinases (Millipore's Kinase Profiler) showed that 500 nM AZ-23 significantly inhibited (>75% inhibition) only a small subset of these enzymes: 24 nM (FGFR1), 52 nM (Flt3), 55 nM (Ret), 84 nM (MuSk), 99 nM (Lck)

In cell validation

On target activity in cells

Potency in cells:

EC50

1.2 nM

Potency assay (cells):

Modified TRF-based TrkA intact cell assay, multiple phosphospecific cellular end point assays (ELISA-based)

Off target activity in cells

Potency in cells, off target:

EC50

Off target protein and potency (cells):

FGFR1 41 nM

Probe Selectivity in Cell:

Cell selectivity: 41 nM (FGFR1), 4077 nM (IGF1R), >1000 nM (Aurora), >3000 (CSF1R) >5000 nM (InsR, Akt, p70S6k, GSK3b)

In vivo validation

Organism:

Rat, Dog

Dose:

3 mg/Kg IV, 10 mg/Kg PO, Reviewer suggest 50-100 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

1.4 (R), 7.5 (D) h

Systemic clearance:

17 (R), 9 (D) mL/min/kg

Primary Reference

Reference (doi):

10.1021/jm800343j 10.1158/1535-7163.MCT-09-0036

Reference (PMID):

18646745 19509272

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

The two cited publications provide a range of biochemical, cell-based, and in vivo assays demonstrating NTRK1/2/3 inhibition. Biochemical and cellular potency is very high for this small kinase family, and selectivity for NTRK enzymes vs other kinases appears reasonable, with FGFR kinases notable off-targets. While explicit PK parameters were not reported in mice, doses of 50 or 100 mpk QD appear effective in strongly suppressing NTRK activity in vivo. PK data for AZD1332 in rat and dog are available, but additional PK/PD data might be necessary to choose an optimal dosing regimen for studies using these species.

Apr 10 2021 - 12:42pm

AZD1332 is an excellent selective Tropomyosin-related kinase A inhibitor, with proven in vitro and in vivo efficacy.

Apr 19 2021 - 12:02pm

AZD1332

Probe Availability

Probe Information

Target Details

MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA, GP145-TrkB, TRKB, trk-B

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AZD1332

Probe Availability

Probe Information

Target Details

MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA, GP145-TrkB, TRKB, trk-B

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?