GDC-0941

 

 Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	GDC-0941 is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold).
Targets	PI3Kα	PI3Kβ	PI3Kδ	PI3Kγ
IC50	3 nM	33 nM	3 nM	75 nM [1]
In vitro	GDC-0941 is equipotent against PI3Kα and PI3Kδ as well as PI3Kα mutants E545-K and H1047-R, displaying modest levels of selectivity against PI3Kβ (10-fold) and PI3Kγ (25-fold), and greater levels of selectivity against members of PI3K class II, III, and IV, including C2β, Vps34, DNA-PK, and mTOR. GDC-0941 potently inhibits the phosphorylation of Akt in U87MG, PC3, and MDA-MB-361 cells with IC50 of 46 nM, 37 nM, and 28 nM, respectively. GDC-0941 inhibits the proliferation of U87MG, A2780, PC3, and MDA-MB-361 cells with IC50 of 0.95 μM, 0.14 μM, 0.28 μM, and 0.72 μM, respectively. [1] GDC-0941 treatment potently inhibits the proliferation of both trastuzumab-sensitive and -insensitive HER2-amplified cells with IC50 of 149-944 nM. GDC-0941 inhibits proliferation of HER2-amplified cells that harbor PIK3CA mutations with IC50 of <500 nM, and effectively inhibits both proliferation and viability of HER2-amplified breast cancer cells that are resistant to trastuzumab due to PTEN loss. [2] GDC-0941 significantly inhibits the growth of HCT116, DLD1 and HT29 cells with GI50 of 1081 nM, 1070 nM and 157 nM, respectively. [3] GDC-0941 inhibits tumor cell proliferation, induces apoptosis and suppresses centroblast population. [4]
In vivo	Administration of GDC-0941 at 75 mg/kg/day displays significant inhibitory effect against established human U87MG glioblastoma xenografts in female NCr athymic mice, with tumor growth inhibition of 83%. [1] Oral administration of GDC-0941 at 150 mg/kg/day inhibits the growth of HER2-amplified, trastuzumab-resistant MDA-MB-361.1 xenografts in mice, and significantly delays the tumor progression, in association with potent induced apoptosis in tumors. [2] GDC-0941 (75 mg/kg/day) treatment for 2 weeks induces ~40% reduction in tumor volume of spontaneous B-cell follicular lymphomas developed in PTEN+/-LKB1+/hypo mice, accompanied by ablation of phosphorylation of Akt, S6K and SGK (serum and glucocorticoid protein kinase) protein kinases. [4]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Scintillation proximity assay

Recombinant human PI3Kα, PI3Kβ, and PI3Kδ are coexpressed in a Sf9 baculovirus system with the p85α regulatory subunit and purified as GST-fusion proteins using affinity chromatography on glutathione-sepharose. Recombinant human PI3Kγ is expressed as monomeric GST-fusions and purified similarly. GDC-0941 is dissolved in DMSO and added to 20 mM Tris-HCl (pH 7.5) containing 200 μg yttrium silicate (Ysi) polylysine SPA beads, 4 mM MgCl2, 1 mM dithiothreitol (DTT), 1 μM ATP, 0.125 μCi [γ-33P]-ATP, and 4% (v/v) DMSO in a total volume of 50 μL. The recombinant GST-fusion of PI3Kα (5 ng), PI3Kβ (5 ng), PI3Kδ (5 ng), or PI3Kγ (5 ng) is added to the assay mixture to initiate the kinase reaction. After incubation for 1 hour at room temperature, the kinase reaction is terminated with 150 μL PBS. The mixture is then centrifuged for 2 minutes at 2000 rpm and read using a Wallac Microbeta counter. The reported IC50 values are calculated using a sigmoidal, dose-response curve fit in MDL Assay Explorer.

Cell Assay: ^[2]

Cell lines	SKBR-3, BT474-M1, AU-565, HCC-1419, ZR75-30, KPL-4, JIMT-1, BT474-EEI, HCC-1954, MCF-7, CALU-3, SKOV-3, and MKN-7 cells
Concentrations	Dissolved in DMSO, final concentrations ~10 μM
Incubation Time	48 and 72 hours
Method	Cells are exposed to various concentrations of GDC-0941 for 48, and 72 hours. Proliferation/viability of cells is detected by using the CellTiter-Glo Luminescent Cell Viability Assay. The pAkt (Ser473), cleaved caspase-3, and cleaved PARP are analyzed by western blot. The Caspase-Glo 3/7 assay and the Cell Death Detection ELISAplus assay are used to detect caspase 3/7 activity, and apoptosis, respectively.

Animal Study: ^[2]

Animal Models	NCR nude mice implanted with MDA-MB-361.1 cells, and SCID, C.B-17/IcrHsd-Prkdcscid mice implanted subcutaneously with BT474-M1 cells
Formulation	Dissolved in 10% DMSO, 5% Tween 20, 85% water
Dosages	~150 mg/kg/day
Administration	Oral gavage

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01240226	Completed	Healthy Volunteer	Genentech	2010-11	Phase 1
NCT01437566	Recruiting	Breast Cancer	Genentech	2011-10	Phase 2
NCT01474668	Completed	Healthy Volunteer	Genentech	2011-10	Phase 1
NCT01493843	Recruiting	Non-Small Cell Lung Cancer	Genentech	2012-01	Phase 2
NCT01740336	Recruiting	Breast Cancer	Genentech	2013-02	Phase 2

Chemical Information

Download GDC-0941 SDF

Chemical Name	2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.51364	5.1364	10.2728	15.4092

Customer Reviews (7)

Click to enlarge	Rating
	Source	J Cell Sci, 2012, 125(Pt 5), 1259-73.. GDC-0941 purchased from Selleck
	Method	Western Blot
	Cell Lines	NMuMG cells
	Concentrations	1 μM
	Incubation Time	1 h
	Results	GDC-0941, a specific inhibitor of the class IA PI3K, similarly blocked the TGF-b-induced Akt(S473) phosphorylation, confirming the role of PI3K in the induction of mTORC2 kinase activity by TGF-β (Fig. C).

Product Citations (30)

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  Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML. [Gibbs KD Jr, et al. Cell Stem Cell 2012;10(2):210-7]

  
  PubMed: 22305570


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  Amplification of CRKL Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non–Small Cell Lung Cancers. [Cheung HW, et al. Cancer Discov 2011;1(7):608-25]

  
  PubMed: 22586683


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  PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. [Ilic N, et al. Proc Natl Acad Sci U S A 2011;108(37):E699-708]

  
  PubMed: 21876152
  
   


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