Chemical Properties
Pale Yellow Solid
Uses
PF-04691502 is an ATP-competitive PI3K/mTOR inhibitor with IC50 of 32 nM and also inhibits Akt T308/S473 with IC50 of 7.5 nM/3.8 nM.
Uses
PF-04691502 is an potent and selective inihibitor of PI3K and mTOR Kinases with antitumor activity.
Biological Activity
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]
Enzyme inhibitor
This ATP-competitive PI3K/mTOR dual inhibitor (FW = 325.49 g/mol; CAS 1013101-36-4; Solubility = 14 mg/mL DMSO, < 1 mg/ML H2O), also systematically named 2-amino-8-((1R,4R)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)- one, potently inhibits recombinant Class-I PI3Kα (Ki = 1.8 nM), PI3Kβ (Ki = 2.1 nM), PI3Kδ (Ki = 1.6 nM), PI3Kγ (Ki = 1.9 nM), and mTOR (Ki = 16 nM) in biochemical assays, with little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 also suppresses avian fibroblast transformation mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF- 04691502 reduces phosphorylation of AKT T308 (IC50 = 7.5–47 nM) and AKT S473 (IC50 = 3.8–20 nM) and inhibits cell proliferation (IC50 = 180– 310 nM). PF-04691502 also inhibite mTORC1 activity within cells, asmeasured by PI3K-independent, nutrient-stimulated assay (IC50 = 32 nM) and inhibited the activation of PI3K and mTOR downstream effectors, including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Shortterm exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 also induces cell cycle G1 arrest, concomitant with upregulation of p27 Kip1 and reduction of retinbalstoma protein, or Rb. At doses below the maximal tolerable dose, PD-0325901 potently inhibits tumor growth, when Kras and/or PI3K are drivers of tumor growth and progression.
in vivo
Nude mice bearing U87MG tumors are administered orally once a day with PF-04691502 at 0.5, 1, 5, and 10 mg/kg (maximum tolerated dose, MTD). Treatment with 10 mg/kg results in a significant reduction of P-AKT(S473) levels at 1 hour postdosing, and persistent inhibition is observed for 8 hours. P-AKT(S473) recovers to above baseline 24 hours after 10 mg/kg treatment. For P-S6RP(S235/236), a similar inhibition time course is observed, but after 24 hours of treatment, P-S6RP levels remain lower than vehicle tumors. Modulation of the AKT downstream effector, P-PRAS40(T246), and mTOR downstream effector, P-4EBP1(T37/46), is observed. The PF-04691502-treated tumors are also evaluated by immunohistochemistry for levels of P-AKT(S473), total AKT, P-S6RP, and total S6RP. Phosphorylation of AKT and S6RP are significantly reduced at 4 hours after a single dose of PF-04691502 at 10 mg/kg. Dose-dependent tumor growth inhibition (TGI) is obtained in the U87MG xenograft model and approximately 73% TGI is observed at the MTD dose of 10 mg/kg[1].
IC 50
PI3Kδ: 1.6 nM (Ki); PI3Kα: 1.8 nM (Ki); PI3Kγ: 1.9 nM (Ki); PI3Kβ: 2.1 nM (Ki); mTOR: 16 nM (Ki)
References
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
