AZD-6482

Protein target name:

PIK3CB

Mechanism of action:

Inhibitor, ATP competitive

Recommended Concentration for use in cells:

0.1 – 0.5 uM

Probe Availability

TOCRIS

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Lipid kinase

Subclass:

Class I

HUGO ID:

HGNC:8976

Entrez gene ID:

5291

UNIPROT ID:

P42338

Target alias:

PI3K; PIK3C1; P110BETA; PI3KBETA

Probe Details

Chemical Probes Portal ID:

CPP2064

Probe alias:

KIN-193, 4urk

PubChem CID:

44137675

ChEMBL ID:

CHEMBL2165191

SMILES string:

OC(C1=C(N[C@@H](C2=CC(C)=CN3C2=NC(N4CCOCC4)=CC3=O)C)C=CC=C1)=O

InChi Key:

IRTDIKMSKMREGO-OAHLLOKOSA-N

PAINs evaluation:

PAINS-Free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

0.69 nM

Potency assay:

In Vitro kinase assay measurements against recombinant PI3Ks and PIKK using SelectScreen (Invitrogen)

Off target activity

Potency (off target):

IC50

Off target protein and potency:

PI3Ka 136 nMPI3Kd 13.6 nMPI3Kg 47.8 nMDNA-PK 53.7 nMPI3K-C2b 54.1 nM

Potency assay (off target):

In Vitro kinase assay measurements against recombinant PI3Ks and PIKK using SelectScreen (Invitrogen)

Probe Selectivity in Vitro:

In Vitro kinase assay showed that AZD-6482 has 200-, 20-, and 70-fold selectivity over p110α, p110δ, and p110γ isoforms, respectively. Exhibit selectivity of approximately 80-fold over PI3K-C2 and DNA-PK and more than 1,000-fold over other PI3K-related kinases. profiling of AZD-6482 against a panel of 433 kinases using the KinomeScan approach (DiscoverX) showed that AZD-6482 is highly selective.

In cell validation

On target activity in cells

Potency in cells:

IC50

100-500 nM

Potency assay (cells):

TR-FRET–based assay termed LanthaScreen

Off target activity in cells

Probe Selectivity in Cell:

Tested cell proliferation on a large panel of 422 cancer cell lines using high-throughput tumor cell line profiling. 35% of cell lines with PTEN mutations (20 of 57) and 16% of cell lines with wild-type PTEN (58 of 365) were sensitive to AZD-6482 with a threshold of EC50 less than 5 μmol/L.

In vivo validation

Organism:

Swiss Albino Mice

Dose:

1 mg/Kg (IV)10 mg/Kg (PO)10 mg/Kg (IP)

Route of delivery:

Oral

Plasma half life:

2.75 h (IV)1.1 h (IP)

Systemic clearance:

148 mL/min/Kg (IV)

Fraction of probe bound to plasma protein:

6.85 %

Cmax:

780 ng/mL (IV)74.1 ng/Kg (PO)2074 ng/Kg (IP)

Tmax:

0.25 h (PO)0.08 h (IP)

Primary Reference

Reference (doi):

10.1158/2159-8290.CD-12-0003 10.1111/j.1538-7836.2012.04898.x

Reference (PMID):

22588880 22906130

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

Given that the profiling data available at this point uses an in vitro affinity binding assay that does not use ATP, it is difficult to assess the intracellular selectivity profile (which may very well be even better). That said, the probe appears to have decent selectivity within and outside the PI3K family. The fact that the probe appears to be selectively active against tumours driven by PTEN loss, only when they do not also have a p110 alpha activating mutation, adds to the promise and utility of this probe. Highest utility is likely to be in systems with low expression of, and biological process dependence on, the delta and gamma isoforms.

Nov 23 2020 - 8:53am

AZ6482 is a highly selective and potent chemical probe for PI3Kbeta. It is suitable for study the role of the target in model cell systems and animal studies.

Dec 8 2020 - 10:10am

AZD-6482 is a suitable chemical probe for assessing PIK3CB (PI3Kbeta) function. The compound is 8-fold selective over PI3Kdelta in in vitro assays and so care should be taken when used in cellular studies to differentiate PI3Kbeta from PI3Kdelta activity in certain contexts.

Dec 18 2020 - 10:17am

AZD-6482

Probe Availability

Probe Information

Target Details

PI3K; PIK3C1; P110BETA; PI3KBETA

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AZD-6482

Probe Availability

Probe Information

Target Details

PI3K; PIK3C1; P110BETA; PI3KBETA

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?