PI-103 Inhibitor CAS No. 371935-74-9

Cat. No.	Name	Size	Price
KI0063	PI-103	5 mg	$110
	PI-103	10 mg	$196
	PI-103	25 mg	$308
	PI-103	50 mg	$484
	PI-103	100 mg	$774

Chemical Characteristic

Product Name	PI-103
CAS No.	371935-74-9
Molecular Weight	348.36
Formula	C₁₉H₁₆N₄O₃
Chemical Name	Phenol, 3-[4-(4-morpholinyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]-
Smiles	c1(cc(ccc1)c1nc2c(c(n1)N1CCOCC1)oc1c2cccn1)O
Chemical Structure

Biological activities

PI-103 is a dual inhibitor of phosphatidylinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). PI-103 inhibits mTORC1, mTORC2 and PI3K with IC50s of 20, 83 and 8 nM, respectively. ^[1] In vitro, in human leukemic cell lines and in primary blast cells from acute myelogenous leukemia (AML) patients, PI-103 inhibits constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 is essentially cytostatic for cell lines and induces cell cycle arrest in the G1 phase. 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 has additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. ^[2] PI-103 induces proliferative arrest in a panel of glioma cell lines assayed by flow cytometry. PI-103 inhibits mTOR, and blocks activation of p-Akt in response to mTOR inhibition. PI-103 also blocks proliferation in a broad range of glioma cell lines. ^[3] PI-103 inhibits in vitro cell growth for proliferation of 37-31E and 37-31E-F3 melanoma cell lines. PI-103 inhibits Akt phosphorylation in response to hepatocyte growth factor (HGF) by 50% at 17.5 nM. PI-103 and sorafenib cooperate inhibiting Akt and extracellular regulated protein kinases (Erk) 1/2 phosphorylation and in vitro cell growth for proliferation in response to HGF in a cell line dependent manner. PI-103 induces the anti-apoptotic BH3 family proteins Mcl1, Bcl2 and Bcl_{xL favoring, the in vitro survival of sorafenib treated melanoma cells. ^[4] PI-103 inhibits PI3K activity and reduces AKt phosphorylation. Continuous exposure to PI-103 inhibits tumor cell clonogenicity. Inhibition of class I PI3K activity with PI-103 reduces radiation survival of tumor cells with EGFR overexpression or RAS mutation. Tumor cells with activated PI3K are radiosensitized by PI-103. PI-103 sensitization is accompanied by increased G2 delay and persistence of γH2AX foci. ^[5] PI-103 shows significant activity in vivo, reducing average tumor size by 4-fold after 18 days. And PI-103 treatment is cytostatic to glioma xenografts in vivo. ^[3] PI-103 induces immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. ^[4]}

Protocols

PI-103 is dissolved as concentrated stock solution in DMSO and stored at -80°C. ^[5]

References

[1] Guertin DA, et al. The pharmacology of mTOR inhibition. Sci Signal. 2009, 2(67): pe24. [2] Park S, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia. 2008, 22(9): 1698-1706. [3] Fan QW, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell. 2006, 9(5): 341-349. [4] L?pez-Fauqued M, et al. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010, 126(7): 1549-1561. [5] Prevo R, et al. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res. 2008, 68(14): 5915-5923.

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