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PI-103

PI-103 is a potent, ATP-competitive PI3K inhibitor of DNA-PK, p110α, mTORC1, PI3KC2β, p110δ, mTORC2, p110β, and p110γ with IC50 of 2 nM, 8 nM, 20 nM, 26 nM, 48 nM, 83 nM, 88 nM and 150 nM, respectively.

Catalog No.S1038
5 5 4 Reviews 5 Product Citations
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PI-103 Chemical Structure
Molecular Weight: 348.36

Validation & Quality Control

Customer Reviews(4)

Quality Control & MSDS

Related Compound Libraries

PI-103 is available in the following compound libraries:

Inhibitor Library (96-well) Kinase Inhibitor Library (96-well) Chemical Library (96-well) Cambridge Cancer Compound Library(96-well)

Product Information

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  • Research Area
  • PI-103 Mechanism

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description PI-103 is a potent, ATP-competitive PI3K inhibitor of DNA-PK, p110α, mTORC1, PI3KC2β, p110δ, mTORC2, p110β, and p110γ with IC50 of 2 nM, 8 nM, 20 nM, 26 nM, 48 nM, 83 nM, 88 nM and 150 nM, respectively.
Targets DNA-PK p110α mTORC1 PI3KC2β p110δ
IC50 2 nM 8 nM 20 nM 26 nM 48 nM [1]
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]
Clinical Trials
Features PI-103 represents the first potent, synthetic mTOR inhibitor.

Protocol(Only for Reference)

Kinase Assay: [1]

Assay of p110 kinase Reactions are initiated by the addition of ATP containing 10 μCi of γ- 32P-ATP to a final concentration 10 or 100 μM, and allowed to proceed for 20 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 μL 1 N HCl followed by 160μL CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase transferred to a new tube using a gel loading pipette tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3-4 hours in a 65:35 solution of n-propanol:1 M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen, and quantitated. For PI-103, kinase activity is typically measured at 10-12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (100 μM). For PI-103 showing significant activity, IC50 determinations are repeated two to four times, and the reported value is the average of these independent measurements.

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 °C).

Animal Study: [2]

Animal Models 6- to 12-week-old Balbc nu/nu mice bearing U87MG:ΔEGFR cells
Formulation 50% DMSO
Dosages 5 mg/kg
Administration Administered via i.p.
1

References

Chemical Information

Download PI-103 SDF
Molecular Weight (MW) 348.36
Formula

C19H16N4O3
CAS No. 371935-74-9, 371935-79-4 (HCl)
Synonyms N/A
Solubility (25°C)
  • DMSO 24 mg/mL
  • Water <1 mg/mL
  • Ethanol <1 mg/mL
Storage 2 years -20°CPowder
2 weeks4°Cin DMSO
6 months-80°Cin DMSO
Chemical Name Phenol, 3-[4-(4-morpholinyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]-
Molarity Calculator Dilution Calculator Molecular Weight Calculator

Research Area

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)

Click to enlarge 		Rating
Source Saraswati Sukumar of Johns Hopkins University School of Medicine, PI-103 purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations
Incubation Time 1 h
Results PI-103 treatment resulted in a reduction of Akt phosphorylation in T47D cells.

Click to enlarge 		Rating
Source Mol Carcinog, 2012, ahead of print. PI-103 purchased from Selleck
Method MTT assay
Cell Lines MCF7 cells
Concentrations 0.01-1 μM
Incubation Time 48 h
Results Knockdown of BRCA1 can sensitize the MCF7 cells to Perifosine in a dose-dependent manner (Figure A). BRCA1-KD also sensitizes the MCF7 cells to dual PI3K/mTOR inhibitors, such as PI-103 or BEZ235 (Figure B, D). Another inhibitor, PIK-75 which specifically inhibits PI3Ka and PI3Kg, but not mTOR, also showed similar effects on proliferation of BRCA1-KD MCF7 cells (Figure C).

Click to enlarge 		Rating
Source Dr. Zhang of Tianjin Medical University. PI-103 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-1 nM
Incubation Time 24 h
Results PI-103 treatment resulted in a reduction of Akt phosphorylation in Breast cancer cells.

Product Citations (5)

  • 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

  • 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

  • Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR. [Chen SM, et al. Biochem Pharmacol 2012;83(9), 1183-1194]

    PubMed: 22305748

  • Prophylactic lithium alleviates postoperative cognition impairment by phosphorylating hippocampal glycogen synthase kinase-3β (Ser9) in aged rats. [Zhao L, et al. Exp Gerontol 2011;46(12):1031-6]

    PubMed: 21945291

  • Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. [Yi YW, et al. Mol Carcinog 2012;ahead of print]

    PubMed: 22488590

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions
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Related DNA-PK Inhibitors

  • ABT-737

    ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM, respectively.

  • BEZ235 (NVP-BEZ235)

    BEZ235 (NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor of p110α, p110γ, p110δ and p110β with IC50 of 4 nM, 5 nM, 7 nM and 75 nM, respectively, and also inhibits ATR with IC50 of 21 nM.

  • Deforolimus (Ridaforolimus)

    Deforolimus (Ridaforolimus, AP23573, MK-8669) is a selective mTOR inhibitor with IC50 of 0.2 nM.

  • GDC-0941

    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.

  • ZSTK474

    ZSTK474 is a potent pan-class I PI3K inhibitor with IC50 of 37 nM.

  • LY294002

    LY294002 is a PI3K inhibitor for p110α, p110δ and p110β with IC50 of 0.5 μM, 0.57 μM and 0.97 μM, respectively.

  • XL147

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  • TGX-221

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  • PIK-75

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