AZD1152

Reagent Authentication Certificate:

Chemical Probes Portal AZD1152.pdf

Protein target name:

AURKB

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

Up to 100 nM

Probe Availability

MedChem Express (722544-51-6)

Abcam (722544-51-6)

MilliporeSigma (722544-51-6)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Other

HUGO ID:

HGNC:11390

Entrez gene ID:

9212

UNIPROT ID:

Q96GD4

Target alias:

AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5, aurkb-sv1, aurkb-sv2

Probe Details

Chemical Probes Portal ID:

CPP118

Probe alias:

Barasertib, AZD-1152

PubChem CID:

11497983

ChEMBL ID:

CHEMBL415049

SMILES string:

CCN(CCCOC1=CC2=C(C=C1)C(=NC=N2)NC3=NNC(=C3)CC(=O)NC4=CC(=CC=C4)F)CCOP(=O)(O)O

InChi Key:

GBJVVSCPOBPEIT-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H NMR (DMSO): ä 10.53 (s, 1H), 8.57 (s, 1H), 8.54 (d, 1H), 7.62 (d, 1H), 7.37 (m, 2H), 7.27 (s, 1H), 7.21 (d, 1H), 6.88 (m, 1H), 6.65 (s, 1H), 4.27 (t, 2H), 4.05 (m, 2H), 3.75 (s, 2H), 3.24 (m, 2H), 3.21 (t, 2H), 3.13 (q, 2H), 2.18 (m, 2H), 1.24 (t, 3H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

<0.001 uM

Potency assay:

AZD1152 (Compound 5), the prodrug for Compound 34 (AZD1152-HQPA), inhibits AURKB in vitro with an IC50 < 0.001 uM.

Structure-activity relationship:

Yes

Off target activity

Potency (off target):

Off target protein and potency:

AURKC 17 nMAURKBA 1.4 uMLCK 1.7 uMKDR 1.8 uMPHK 1.8 uMZAP70 8.2 uM

In cell validation

On target activity in cells

Potency in cells:

IC50

<0.001 uM

Potency assay (cells):

In-cell (SW620 cells) protein substrate phosphorylation (phospho Histone 3)

Target engagement assay (cells):

Indirect, in cell protein substrate (Histone 3) phosphorylation

In vivo validation

Organism:

Swiss nude (nu/nu) mice

Dose:

150 mg/kg

Route of delivery:

IntravenousSubcutaneous

Plasma half life:

4.9-5.8 h

Systemic clearance:

14 mg/mL/kg (in rat)

Tmax:

2 min

Organ of Interest

Organ (O):

tumor xenograft (SW620 cells)

Target engagement assay:

Indirect, protein substrate phosphorylation assay (phospho H3)

Primary Reference

Reference (doi):

10.1182/blood-2007-02-073700 J Med Chem

Reference (PMID):

17495131 17373783

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

I would like to see a more comprehensive screen of this probe against more than 50 kinases to confirm its broad selectivity. IC50 is listed at 0.37 nM. It is ~3700-fold more selective for Aurora B over Aurora A. AZD1152-HQPA is the active metabolite of AZ1152.

Jun 11 2016 - 4:33am

AZD1152 is a phosphate pro-drug that is rapidly cleaved to the active alcohol. The active alcohol is a potent inhibitor of AURB and AURC. We have dosed AZD1152 in tumor xenograft models in mice using IP administration (100 mg/kg, dosed once daily for 3 consecutive days) and seen robust efficacy in sensitive models (e.g., Lymphoma DOOH2 cell line). The AZD1152 alcohol is significantly less active in P-gp- and BCRP-expressing cell lines, most likely due to drug efflux.

Jun 11 2016 - 4:33am

AZD1152 is a phosphate prodrug designed for in vivo studies only. The active form is compound 34 in the corresponding J Med Chem paper, with Aurora B inhibition IC50 <1 nM and the corresponding functional effect in SW620 cells of IC50 17 nM. For in vitro, cell-based studies, Compound 34 should be used since cleavage of the phosphate in AZD1152 might not occur in a cellular system. The compound is very selective based on profiling in the Ambit kinome panel where less than 10 kinases (example EPHB6, FLT3 (more potent than Aurora B)), have a KD within 10X of that for Aurora B. Any kinase reported as an off target within 100X could have functional effect in cellular environment if the Km for ATP is large.

Aug 29 2016 - 2:18pm

AZD1152

Probe Availability

Probe Information

Target Details

AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5, aurkb-sv1, aurkb-sv2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AZD1152

Probe Availability

Probe Information

Target Details

AIK2, AIM-1, AIM1, ARK2, AurB, IPL1, PPP1R48, STK12, STK5, aurkb-sv1, aurkb-sv2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?