Gedatolisib

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Chemical Structure| 1197160-78-3 同义名 : PKI-587;PF-05212384;PF5212384;PK-1587
CAS号 : 1197160-78-3
货号 : A178133
分子式 : C32H41N9O4
纯度 : 99%
分子量 : 615.726
MDL号 : MFCD16875679
存储条件：

Pure form Sealed in dry,Room Temperature

In solvent -20°C:3-6个月-80°C:12个月
溶解度 : -
动物实验配方：

IP 6.25% DMSO+2% Tween80+40% PEG300+water 1 mg/mL clear

PO 0.5% CMC-Na 20 mg/mL suspension

生物活性
靶点

  • p110γ

    PI3Kγ, IC50:5.4 nM

  • p110α

    PI3Kα, IC50:0.4 nM

  • mTOR

    mTOR, IC50:1.6 nM
描述 PI3Ks are lipid kinases that phosphorylate PIP2 to PIP3. The catalytic subunits of class IA PI3Ks consists of PI3Kα, PI3Kβ and PI3Kδ isoforms. Among these isoforms, PIK3CA encoding the PI3Kα subunit, is mutated and/or overexpressed in breast, ovarian, colorectal, glioblastoma, and gastric cancers. The protein mTOR is one of the PI3K related kinases (PIKKs) which share a conserved kinase domain with PI3Ks. PI3K/Akt/mtor signaling is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. Gedatolisib, also called as PF-05212384 or PKI-587, is a highly potent PI3K/mTOR dual inhibitor with IC50 of 0.4 nM, 5.4 nM and 1.6 nM (measured by fluorescent polarization) on PI3Kα, PI3Kγ and mTOR, respectively. In vitro, Gedatolisib inhibits pAkt-T308 (IC50=8 nM) and pAkt-S473 (IC50 <10nM), as well as induces apoptosis in MDA-361 cells. Meanwhile, the phophorylation of Akt kinase effector (like proteins GSK3 kinase, ENOS and PRAS40) and mTORC1 effector (like p70S6K and 4EBP1 phosphorylation) can be suppressed by Gedatolisib at concentrations less than 30 nM. Administration of Gedatolisib i.v. at 20 mg/kg on an intermittent regimen (days 1, 5, 9) can regress large staged (∼900 mm3) tumors in MDA-361 tumor model[1]. Up to now, Gedatolisib is used in the clinical trial study of Breast, endometrial, colorectal, ovarian, and H&N cancers, NSCLC, SCLC, AML[2].
作用机制 PKI-587 can dock in the ATP binding site of PI3K and form the critical hinge region hydrogen-bond to Val851 through a morpholine oxygen[1].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human PC3 cells Growth inhibition assay 72 h Growth inhibition of human PC3 cells after 72 hrs, IC50=0.011 μM 21763134
MDA-MB-361 cells Cytotoxicity assay Cytotoxicity against human MDA-MB-361 cells, IC50=0.004 μM 20166697
MDA-MB-361 cells Function assay Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.008 μM 20166697
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.62mL

0.32mL

0.16mL

8.12mL

1.62mL

0.81mL

16.24mL

3.25mL

1.62mL
参考文献

[1]Venkatesan AM, Dehnhardt CM, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45.

[2]Zhao HF, Wang J, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017 Jun 7;16(1):100.