PI-103

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

Biological Activity

Description	PI-103 is a multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM, less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM.
Targets	p110α	p110β	p110δ	p110γ	mTOR	DNA-PK
IC50	2 nM	3 nM	3 nM	15 nM	30 nM	23 nM [3]
In vitro	PI-103 potently inhibits both the rapamycin-sensitive (mTORC1) and rapamycin-insensitive (mTORC2) complexes of the protein kinase mTOR. [1] PI-103 inhibits constitutive and growth factor-induced PI3K/Akt, as well as mTORC1 activation. [2] In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. PI-103 inhibits p110α >200-fold more potently than p110β. PI-103 also potently blocks production of PI(3,4)P2 and PIP3 in adipocytes and PIP3 in myotubes. [2] PI-103 inhibits phosphorylation of Akt with an IC95 100-fold lower than that for LY294002. Strikingly, PI-103 completely protects animals from insulin-stimulated decline in blood glucose. PI-103 has additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. [2]
In vivo	When tumors reach 50-100 mm3, animals are randomized and treated with vehicle or PI-103. PI-103 exhibits significant activity, decreasing average tumor size by 4-fold after 18 days. [2] Mice treated with PI-103 have no obvious signs of toxicity premorbidly (based on body weight, food and water intake, activity, and general exam) or at necropsy. Treated tumors display decreased levels of phosphorylated Akt and S6, consistent with blockade of p110α and mTOR. PI-103 treatment is cytostatic to glioma xenografts. [2]
Features	The first potent, synthetic mTOR inhibitor.

Protocol(Only for Reference)

Kinase Assay: ^[3]

Enzyme Assays

Phosphatidylinositide 3-kinase inhibitory activity was determined using a scintillation proximity assay in the presence of 1 μmol/L ATP. Inhibition of mTOR protein kinase was determined using a TR-FRET-based LanthaScreen method from Invitrogen. Compounds were assayed at a maximum concentration of 10 μmol/L in the presence of 1 μmol/L ATP, and IC50 values were determined using GraphPad Prism software.

Cell Assay: ^[2]

Cell lines	U87MG cells
Concentrations	0.5 μM
Incubation Time	24 hours
Method	U87MG cells are treated with PI-103 for 24 hours. Cell death is quantified by colorimetric determination of LDH activity using a cytotoxicity detection kit. Percentage of cell death (mean of three 12-well plates per experimental point) is calculated [(experimental value- low control)/(high control -low control) × 100], where the low-control cells are DMSO treated and high-control cells are Triton treated (1% Triton X-100, 30 min, 37 °

Animal Study: ^[2]

Animal Models	6- to 12-week-old Balbc nu/nu mice bearing U87MG:ΔEGFR cells
Dosages	5 mg/kg
Administration	Administered via i.p.
Solubility	1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL

1

References

Chemical Information

Download PI-103 SDF

Chemical Name	Phenol, 3-[4-(4-morpholinyl)pyrido[3,2:4,5]furo[3,2-d]pyrimidin-2-yl]-

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.34836	3.4836	6.9672	10.4508

Customer Reviews (4)

Click to enlarge	Rating
	Source	Mol Carcinog 2012.April ahead of print. PI-103 purchased from Selleck
	Method	Western blot
	Cell Lines	MCF7 cells
	Concentrations	0-1 μM
	Incubation Time	24 h
	Results	In BRCA1-KD MCF7 cells, treatment of PI-103, a PI3K/mTOR inhibitor, abolished phosphorylation of AKT and its substrate GSK3b, in a dose dependent manner (Figure A). Treatment of PI-103 reduced the phosphorylation of AKT in all BRCA1 mutant breast cancer cells tested (Figure B). Phosphorylations of downstream targets of AKT, such as phospho-GSK3b (S9) and phospho-BAD(S112) were also reduced by PI-103 treatment. Phosphorylation of mTOR at S2448, which is also known to be phosphorylated by AKT, was also reduced by PI-103 resulting in reduced phosphorylation of S6 ribosomal protein at S235/236 (Figure B). The effect of PI-103 was much more potent than LY294002 in MDA-MB-436 cells (Figure B)

Product Citations (10)

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  PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. [Shepherd C, et al. Leukemia 2013;27(3):650-60]

  
  PubMed: 23038273


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  Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts. [Fuka G, et al. Leukemia 2012;26(5):927-33]

  
  PubMed: 22094587


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  Supramolecular nanoparticles that target phosphatidylinositol-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy. [Kulkarni A, et al. Cancer Res 2013;73(23):6987-97]

  
  PubMed: 24121488