AZD-6482

AZD-6482 : ATP competitive inhibitor of PIK3CB

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

PIK3CB

Inhibitor, ATP competitive

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Probe Availability:

In Vitro Validations

Uniprot ID: P42338

Target Class: Lipid kinase

Target SubClass: Class I

Potency: IC50

Potency Value: 0.69 nM

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

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

Target aliases:

Phosphatidylinositol 4,5-bisphosphate 3-kinase cat ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 PI3Ka 136 nM, PI3Kd 13.6 nM, PI3Kg 47.8 nM, DNA-PK 53.7 nM, PI3K-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.

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.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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.

(last updated: 23 Nov 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 8 Dec 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 18 Dec 2020 )