Pictilisib

Reagent Authentication Certificate:

Chemical Probes Portal GDC-0941.pdf

Protein target name:

PIK3CA, PIK3CD

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

10 nM - 500 nM

Probe Availability

MedChem Express (957054-30-7)

Abcam (957054-30-7)

Cayman (957054-30-7)

Probe Information

Target and Probe Information

Target Details

Target class:

Lipid kinase

Subclass:

Class I

HUGO ID:

HGNC:8975 HGNC:8977

Entrez gene ID:

5290 5293

UNIPROT ID:

P42336 O00329

Target alias:

CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha

Probe Details

Chemical Probes Portal ID:

CPP96

Probe alias:

GDC-0941

PubChem CID:

17755052

ChEMBL ID:

CHEMBL521851

SMILES string:

CS(=O)(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6

InChi Key:

LHNIIDJUOCFXAP-UHFFFAOYSA-N

Orthogonal probe:

BYL-719PI-3065

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H NMR (CDCl3) δ 2.67-2.71 (m, 4H), 2.81 (s, 3H), 3.29-3.33 (m, 4H), 3.89 (s, 2H), 3.89-3.93 (m, 4H), 4.08-4.12 (m, 4H), 7.41 (s, 1H), 7.51 (t, J ) 7.2 Hz, 1H), 7.60 (d, J ) 8.3 Hz, 1H), 8.28 (d, J ) 7.5 Hz, 1H), 9.02 (s, 1H), 10.10 (s, br,1H)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

10.2 nM

Potency assay:

Potency was also determined in scintillation proximity assays yielding IC50 = 0.003 uM for both PIK3CA and PIK3CD.

Off target activity

Potency (off target):

IC50

Off target protein and potency:

PIK3CB 0.033 uMPIK3CD 0.075 uMC2 beta 0.67 uMVPS34 >10 uMDNA-PK 1.23 uMMTOR Ki(app) = 0.58 uM

Potency assay (off target):

Scintillation proximity assay

Probe Selectivity in Vitro:

Kinase Profiler assessment of 228 protein kinases revealed <50% inhibition at 1 uM for all kinases except FLT3 and TRKA (IC50 = 2.85 uM). Minimal inhibition of 6 P450 isoforms was detected at 25 uM.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.028-0.046 uM

Potency assay (cells):

Inhibition of protein substrate phosphorylation in MDA-MB-361, PC3, and U87MG cells.

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation

In vivo validation

Organism:

NCr athymic mice

Dose:

75 ng/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Indirect: inhibition of protein substrate phosphorylation in xenograft tissue

Primary Reference

Reference (doi):

10.1021/jm800295d

Reference (PMID):

18754654

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

4 review(s)

Rating for use in Model Organisms

4 review(s)

SAB Members

SAB Comments

GDC-0941 is an inhibitor of class I PI3 kinases (IC50 α, β, δ, γ = 3, 33, 3, 75 nM, respectively) with selectivity over class II, III and IV enzymes C2β (670 nM), Vps34 (>10 µM), DNA-PK (1.23 µM) and mTOR (580 nM). Greater than 300-fold selectivity for the α-isoform versus an additional 228 kinases was also described. Cellular activity against tumor cell lines was reported as EC50 = 140-950 nM while inhibition of cellular target engagement (pAkt473) occurred at lower exposures (EC50 = 28-46 nM). In vivo target engagement and tumor growth inhibition were reported following oral administration to mice (25-150 mg/kg/d). This tool is recommended for use in preference to the older, less selective inhibitors such as wortmannin and LY294002.

Jun 12 2016 - 4:09am

Chemical Neighbourhood for QSAR: 129, 47, and 24 molecules similar (>0.80) to GDC-0941 with in vitro affinities for PIK3CA, PIK3CD, and PIK3CB, respectively, were found in public repositories (e.g., ChEMBL).

Jul 13 2016 - 4:29pm

For cell culture, I would recommend confirming class I inhibition without inhibition of the other classes (class II-class IV). However, because cell-free sensitivities of the p110s vary from 3 nM (alpha) to 75 nM (gamma, 25-fold of alpha) and cellular sensitivities of classes II and IV are relatively higher, a careful dose-response study in cells should be conducted before conclusions are drawn from the data.

Jul 14 2016 - 11:07pm

Pictilisib

Probe Availability

Probe Information

Target Details

CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Pictilisib

Probe Availability

Probe Information

Target Details

CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?