4-{6-[(4-methanesulfonylpiperazin-1-yl)methyl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl}-1H-indazole

• ChemBase编号: 72488
• 分子式: C23H27N7O3S2
• 平均质量: 513.63558
• 单一同位素质量: 513.16167976
• SMILES: c1(cccc2c1cn[nH]2)c1nc(c2c(n1)cc(s2)CN1CCN(CC1)S(=O)(=O)C)N1CCOCC1
• Canonical SMILES: CS(=O)(=O)N1CCN(CC1)Cc1cc2c(s1)c(nc(n2)c1cccc2c1cn[nH]2)N1CCOCC1
• InChI: InChI=1S/C23H27N7O3S2/c1-35(31,32)30-7-5-28(6-8-30)15-16-13-20-21(34-16)23(29-9-11-33-12-10-29)26-22(25-20)17-3-2-4-19-18(17)14-24-27-19/h2-4,13-14H,5-12,15H2,1H3,(H,24,27)
• InChIKey: LHNIIDJUOCFXAP-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 4-{6-[(4-methanesulfonylpiperazin-1-yl)methyl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl}-1H-indazole
• IUPAC传统名: 4-{6-[(4-methanesulfonylpiperazin-1-yl)methyl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl}-1H-indazole
• 别名: GDC-0941

登记号

• CAS号: 957054-30-7
• PubChem SID: 162037413
• PubChem CID: 17755052

理论计算性质

• Acid pKa: 13.191971
• 质子受体: 8
• 质子供体: 1
• LogD (pH = 5.5): 1.62995
• LogD (pH = 7.4): 2.4275908
• Log P: 2.4578528
• 摩尔折射率: 147.1823 cm^3
• 极化性: 54.92992 Å^3
• 极化表面积: 107.55 Å^2
• 可自由旋转的化学键: 4
• 里宾斯基五规则: false

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: PI3K

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1065

Research Area

• Description: Solid tumours, Non-small cell lung cancer

Biological Activity

• Description: GDC-0941 is a potent inhibitor of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ with IC50 of 3 nM, 33 nM, 3 nM and 75 nM, respectively.
• 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. ^[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. Consistently, GDC-0941 inhibits tumor cell proliferation, induces apoptosis and suppresses centroblast population. ^[3]
• 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.

Combination Therapy

• Description: GDC-0941 (50 nM) in combination with Trastuzumab (10 μg/mL) synergistically inhibits the PI3K/Akt pathway with a 67% reduction in pAkt compared to 50 nM GDC-0941 treatment alone, and efficiently blocks the compensatory effect (elevated pHER3) from PI3K inhibition, resulting in a synergistic effect on the proliferation of Trastuzumab-sensitive breast cancer cells. The combination also significantly increases caspase activity and induces apoptosis, reducing the required doses by 4-10 fold compared with GDC-0941 treatment alone. GDC-0941 combined with Trastuzumab is more efficient in inhibition of the trastuzumab-sensitive BT474-M1 xenografts in mice than either of the single agents. ^[2] GDC-0941 in combination with MEK inhibitor either AZD6244 or PD0325901 exhibits greater synergistic growth inhibition against HCT116, DLD1 and HT29 cells, compared with the combinations with NVP-BEZ235, which can be compromised by mTORC1/2 inhibitor KU0063794 due to inhibition of mTOR. ^[4] A Phase I study of GDC-0941 in combination with GDC-0973 in patients with locally advanced or metastatic solid tumors is currently ongoing.

Protocol

• Protocol: 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.
• Protocol: 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
• Methods: 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 ELISA^plus assay are used to detect caspase 3/7 activity, and apoptosis, respectively.
• Protocol: Animal Study ^[2]
• Animal Models: NCR nude mice implanted with MDA-MB-361.1 cells, and SCID, C.B-17/IcrHsd-Prkdc^scid mice implanted subcutaneously with BT474-M1 cells
• Formulation: Dissolved in 10% DMSO, 5% Tween 20, 85% water
• Doses: ~150 mg/kg/day
• Administration: Oral gavage

References

• References: [1] Folkes AJ, et al. J Med Chem, 2008, 51(18), 5522-5532.
• References: [2] Junttila TT, et al. Cancer Cell, 2009, 15(5), 429-440.
• References: [3] García-Martínez JM, et al. Br J Cancer, 2011, 104(7), 1116-1125.
• References: [4] Haagensen EJ, et al. Br J Cancer, 2012, 106(8), 1386-1394.

参考文献

• Junttila TT, et al. Cancer Cell, 2009, 15(5), 429-440.
• Folkes AJ, et al. J Med Chem, 2008, 51(18), 5522-5532.
• García-Martínez JM, et al. Br J Cancer, 2011, 104(7), 1116-1125.
• Haagensen EJ, et al. Br J Cancer, 2012, 106(8), 1386-1394.