PF-04691502

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Background

PF-04691502 is a potent and selective dual PI3K/mTOR (FRAP) inhibitor to phosphorylation of Akt T308 (IC50 = 7.5 nM) and Akt S473 (IC50 = 3.8 nM).[1]PI3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.The functions of PI3Ks most relate to the ability of class I PI3K to activate protein kinase B (PKB, aka Akt) as in the PI3K/AKT/mTOR pathway which is an intracellular signaling pathway directly related to cellular quiescence, proliferation, cancer, and longevity. There are many valuable anti-cancer drug treatment targets within this pathway. And also the p110δ and p110γ isoforms regulate different aspects of immune responses. [2]PF-04691502 is a potential medical drug that functions by inhibiting class I PI3K and mTOR in the PI3K/AKT/mTOR pathway through fluorescence polarization kinase assay, cell,mice and other animal trials, and therefore, through inhibition, results in tumour suppression.[3,4] Short-term exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 induces cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. [5] Antitumor activity of PF-04691502 is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. PF-04691502 inhibits tumor growth at 7 days by 72%. FDG-PET imaging revealed that PF-04691502 reduces glucose metabolism dramatically. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), are also dramatically inhibited following PF-04691502 treatment. [6]

1. Yuan J."PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity". Mol Cancer Ther, 2011, 10(11), 2189-2199.
2. Okkenhaug K. "Signaling by the Phosphoinositide 3-kinase Family in Immune Cells.".Annu. Rev. Immunol, 2013. 17 (2): 675–699.
3. Maira, Sauveur-Michel; Stauffer, Frédéric; Schnell, Christian; García-Echeverría, Carlos. "PI3K inhibitors for cancer treatment: where do we stand ". Biochemical Society Transactions., 2009. 37 (Pt 1): 265–72.
4. Kinross KM. "In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D; Pten Deletion Mouse Model of Ovarian Cancer". Mol Cancer Ther, 2011, 10(8), 1440-1449.
5. Yuan J, Mol Cancer Ther, 2011, 10(11), 2189-21996. Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449