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Pictilisib (GDC-0941)

Pictilisib (GDC-0941)

Item no.	S1065-10mM
Manufacturer	Selleckchem
CASRN	957054-30-7
Amount	10 mM/1 mL
Quantity options	10 mg 1 g 10 g 10 mM/1 mL 200 mg 5 mg 50 mg 5 g
Category	Oncology Metabolism Diabetes Inhibitors & Compound Libraries Small Molecules By Organ Skin Cancer Breast Cancer Brain Cancer Lymphatic System Cancer
Type	Inhibitors
Specific against	other
Smiles	CS(=O)(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	RG7321
Similar products	GDC-0941
Available
Manufacturer - Targets	PI3K
Storage Conditions	2 years -80 in solvent
Molecular Weight	513, 64
Administration	Oral gavage
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
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
Clinical Trials	A Phase I study of GDC-0941 in patients with locally advanced or metastatic solid tumors, Non-Hodgkin's lymphoma, or multiple myeloma (MM) (expansion stage only) for which standard therapy either does not exist or has proven ineffective or intolerable is currently ongoing.
Concentrations	Dissolved in DMSO, final concentrations ca.10 uM
Dosages	ca.150 mg/kg/day
Formulation	Dissolved in 10% DMSO, 5% Tween 20, 85% water
IC50	3 nM, 3 nM, 3 nM, 3 nM, 3 nM, 3 nM
In vitro	GDC-0941 is equipotent against PI3Kalpha and PI3Kdelta as well as PI3Kalpha mutants E545-K and H1047-R, displaying modest levels of selectivity against PI3Kbeta (10-fold) and PI3Kgamma (25-fold), and greater levels of selectivity against members of PI3K class II, III, and IV, including C2beta, 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 uM, 0.14 uM, 0.28 uM, and 0.72 uM, 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 ca.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]
Incubation Time	48 and 72 hours
Kinase Assay	Scintillation proximity assay, Recombinant human PI3Kalpha, PI3Kbeta, and PI3Kdelta are coexpressed in a Sf9 baculovirus system with the p85alpha regulatory subunit and purified as GST-fusion proteins using affinity chromatography on glutathione-sepharose. Recombinant human PI3Kgamma 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 ug yttrium silicate (Ysi) polylysine SPA beads, 4 mM MgCl2, 1 mM dithiothreitol (DTT), 1 uM ATP, 0.125 uCi [gamma-33P]-ATP, and 4% (v/v) DMSO in a total volume of 50 uL. The recombinant GST-fusion of PI3Kalpha (5 ng), PI3Kbeta (5 ng), PI3Kdelta (5 ng), or PI3Kgamma (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 uL 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.
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.
Solubility (25C)	DMSO 44 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	Pictilisib (GDC-0941, RG7321) is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM in cell-free assays, with modest selectivity against p110β (11-fold) and p110γ (25-fold). Pictilisib (GDC-0941) induces autophagy and apoptosis. Phase 2.
Chemical Name	2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3, 2-d]pyrimidine

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