生物活性

• 靶点

  PI3Kβ Ki:2.1nM

  mTOR Ki:16nM

  PI3Kγ Ki:1.9nM

  PI3Kα Ki:1.8nM

  PI3Kδ Ki:1.6nM

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• 描述The phosphoinositide 3-kinase (PI3K) signaling pathway plays a central role in regulating cell growth, proliferation, survival, angiogenesis, metabolism, and motility. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. Dual PI3K/mTOR inhibitors may most effectively block the PI3K pathway, overcome feedback loops, and block PI3K-independent mTOR activation. PF-04691502 inhibited human and mouse PI3Kα with Ki of 1.8 and 1.2 nmol/L, respectively, PI3K isoforms β, δ, and γ with Ki of 2.1, 1.6, and 1.9 nmol/L, respectively, and human mTOR with Ki of 16 nmol/L. PF-04691502 inhibited phosphorylation of AKT at S473 and T308 consistent with the inhibition of phosphorylation of AKT downstream proteins such as FKHRL1 and PRAS40. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC50 of 7.5 – 47 nmol/L and 3.8 – 20 nmol/L, respectively) and inhibited cell proliferation (IC50 of 179 – 313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC50 of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. In a vivo study, PF-04691502 was formulated in 0.5% methylcellulose in water suspension, nude mice bearing U87MG tumors were administered orally once a day with PF-04691502 at 0.5, 1, 5, and 10 mg/kg. Dose-dependent tumor growth inhibition (TGI) was obtained in the U87MG xenograft model and approximately 73% TGI was observed at the MTD dose of 10 mg/kg^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human BT20 cells	-	Function assay	-	Inhibition of AKT phosphorylation at Ser 473 in human BT20 cells, IC50=0.013 μM	23506825
  human SKOV3 cells	-	Proliferation assay	3 days	Antiproliferative activity against human SKOV3 cells after 3 days by CellTiter-Glo assay, IC50=0.29 μM	25139570
  human U87MG cells	-	Proliferation assay	4 days	Antiproliferative activity against human U87MG cells after 4 days by CellTiter-Glo assay, IC50=0.52 μM	25139570

• 动物研究
  剂量	Nude mice: 0.5 mg/kg - 10 mg/kg[3] (p.o.); 10 mg/kg[4] (i.v., q2w)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01347866	Advanced Cancer	Phase 1	Terminated(Refer to Detailed D... more >>escription for documentaion of Termination Statement.) Collapse <<	-	United States, California ... more >> Ronald Reagan UCLA Medical Center Los Angeles, California, United States, 90095-6984 Ronald Reagan UCLA Medical Center Los Angeles, California, United States, 90095 UCLA Medical Center Los Angeles, California, United States, 90095 UCLA Oncology Center Los Angeles, California, United States, 90095 Santa Monica - UCLA Medical Center and Orthopaedic Hospital Santa Monica, California, United States, 90404 UCLA Santa Monica Hematology Oncology Santa Monica, California, United States, 90404 United States, Colorado Anschutz Cancer Pavilion Aurora, Colorado, United States, 80045 University of Colorado Denver (CTRC) Aurora, Colorado, United States, 80045 University of Colorado Hospital Anschutz Inpatient Pavilion Aurora, Colorado, United States, 80045 University of Colorado Hospital Aurora, Colorado, United States, 80045 United States, South Carolina Medical University of South Carolina, Hollings Cancer Center Charleston, South Carolina, United States, 29425 Medical University of South Carolina Charleston, South Carolina, United States, 29425 MUSC, Investigational Drug Services Charleston, South Carolina, United States, 29425 MUSC Health East Cooper Mount Pleasant, South Carolina, United States, 29464 MUSC Specialty Care-North North Charleston, South Carolina, United States, 29406 Canada, Ontario Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Italy Ospedale San Raffaele Milano, Italy, 20132 Spain Hospital General Vall d'Hebron Barcelona, Spain, 08035 Collapse <<
  NCT00445315	Hepatitis C	Phase 1	Completed	-	Belgium ... more >> Pfizer Investigational Site Bruxelles, Belgium, 1070 Germany Pfizer Investigational Site Berlin, Germany, 10117 Pfizer Investigational Site Berlin, Germany, 12351 United Kingdom Pfizer Investigational Site Dundee, United Kingdom, DD1 9SY Collapse <<
  NCT01430585	Early Breast Cancer (Phase 2) ... more >> Advanced Breast Cancer (Phase 1b) Collapse <<	Phase 2	Terminated(See termination rea... more >>son in detailed description.) Collapse <<	-	Belgium ... more >> Pfizer Investigational Site Charleroi, Belgium, 6000 Italy Pfizer Investigational Site Milano, Italy, 20132 Spain Pfizer Investigational Site Barcelona, Spain, 08035 Sweden Pfizer Investigational Site Goteborg, Sweden, 413 45 Pfizer Investigational Site Stockholm, Sweden, 171 76 Collapse <<

• 更多
• 参考文献

• [1] Simmons BH, Lee JH, et al. Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice. Cancer Chemother Pharmacol. 2012 Aug;70(2):213-20.

  [2] Kinross KM, Brown DV, et al. In vivo activity of combined PI3K/mTOR and MEK inhibition in a Kras(G12D);Pten deletion mouse model of ovarian cancer. Mol Cancer Ther. 2011 Aug;10(8):1440-9.

  [3] Yuan J, Mehta PP, Yin MJ, Sun S, Zou A, Chen J, Rafidi K, Feng Z, Nickel J, Engebretsen J, Hallin J, Blasina A, Zhang E, Nguyen L, Sun M, Vogt PK, McHarg A, Cheng H, Christensen JG, Kan JL, Bagrodia S. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther. 2011 Nov;10(11):2189-99. doi: 10.1158/1535-7163.MCT-11-0185. Epub 2011 Jul 12. PMID: 21750219.