Apitolisib

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Chemical Structure| 1032754-93-0 同义名 : GDC-0980; GNE 390; RG 7422
CAS号 : 1032754-93-0
货号 : A281340
分子式 : C23H30N8O3S
纯度 : 98%+
分子量 : 498.601
MDL号 : MFCD20274520
存储条件：

Pure form Keep in dark place, sealed in dry, store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 15 mg/mL(30.08 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

0.5% methylcellulose+0.2% Tween 80+water 30 mg/mL suspension

生物活性
靶点

  • p110γ

    p110γ, IC50:14 nM

  • p110β

    p110β, IC50:27 nM

  • p110α

    p110α, IC50:5 nM

  • p110δ

    p110δ, IC50:7 nM

  • mTOR

    mTOR, Ki app:17 nM
描述 PI3K and mTOR are two critical signaling pathways that of high degree similarity of active sites and thus are important for cell growth and cancer treatment. GDC-0980 is a class 1 PI3K and mTOR kinase inhibitor with IC50 values of 5, 27, 7 and 14 nM for PI3Kα, β, δ and γ isoforms respectively. The Ki of GDC-0980 against mTOR is 17nM. Treatment with 1 μM GDC-0980 could also show >60% inhibition to some additional kinases like Fgr, Mlk1, Syk with IC50 VALUES of 697, 232, 134 nM respectively. In PC-3 and MCF-7 neo/HER2 cell lines, treatment with 1 mg/kg of this drug demonstrated significant antitumor activity and tumor growth delay. Tumor stasis or regressions were also observed with the concentration of 7.5 mg/kg, which further showed a high cellular potency and low plasma clearance[1]. Treatment of GDC-0980 with IC50 <500nM demonstrated 100%, 78%, 88%, 67% and 33% inhibitions to prostate, breast, NSCLC, pancreatic and melanoma cell lines respectively, suggesting different reduction of viability in alternated cancer cells. Furthermore, phosphorylation of all downstream markers was reduced including phospho-Akt (at Thr308, Ser473 sites), phospho-S6 and phospho-ERK. The assessment results of cell cycle markers treated with 0.1 and 0.5 μM GDC-0980 found that Cyclin D1 expressed in most proliferating cells except for KP4 and A375 cell lines. Besides, cleaved PARP was also found in KPL4 and LoVo cell lines, suggesting an earlier apoptotic response to this drug. In a 20 xenograft tumor models, treatment of 5 mg/kg GDC-0980 resulted in 70% loss of body weight and 50% tumor growth inhibitions in 15 of the models. In pharmacokinetic mice model, 2.5 mg/kg of GDC-0980 could delay tumor growth. Tumor stasis and tumor regression were happened at higher concentrations that were 5 mg/kg and 10 mg/kg respectively. In the 2.5 mg/kg concentration group, undetectable GDC-0980 plasma levels was found as well as reduced baseline level of pAkt/tAkt that were 60% and 75% at 5 and 10 mg/kg concentration groups, suggesting GDC-0980 is an effective dual PI3K/mTOR inhibitor[2].
作用机制 GDC-0980 binds to mTORC1 and mTORC2, decreasing phospho-AktThr308 and Ser473, S6K and phospho-S6[2].
细胞研究
细胞系 浓度 检测类型 检测时间 活性说明 数据源
human MCF7.1 cells Proliferation assay Antiproliferative activity against human MCF7.1 cells expressing HER2 gene after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.255 μM 21981714
human PC3 cells Function assay Inhibition of PIK3 gamma-mediated Akt phosphorylation at Ser473 in human PC3 cells by ELISA, IC50=0.036 μM 21981714
human PC3 cells Proliferation assay Antiproliferative activity against human PC3 cells after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.307 μM 21981714
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.01mL

0.40mL

0.20mL

10.03mL

2.01mL

1.00mL

20.06mL

4.01mL

2.01mL
参考文献

[1]Sutherlin DP, Bao L, et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem. 2011;54(21):7579-87.

[2]Wallin JJ, Edgar KA, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011;10(12):2426-36.