A potent, dual PI3K/mTOR inhibitor
PF-05212384 is an inhibitor of PI3K/mTOR with IC50 values of 0.4nM, 6nM, 8nM, 6nM and 1.4nM for PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and mTOR, respectively [1].
PF-05212384 is a pan-PI3K/mTORinhibitor and shows to be highly selective for PI3K and mTOR. Besides the wt P13K, PF-05212384 can also inhibit mutant P13K with IC50 values of 0.6nM for both H1047R and E545K mutants. In cellular assay, PF-05212384 potently inhibits tumor growth in MDA-361 and PC3-MM2 cell lines with IC50 values of 4nM and 13.1nM, respectively. Meanwhile, PF-05212384 suppresses the phosphorylation of PI3K/mTOR signaling pathway proteins in cells. It inhibits the phosphorylation of Akt as well as the Akt effector proteins including GSK3 kinase, ENOS and PRAS 40. Moreover, PF-05212384 has potent anti-tumor activity in a variety of xenograft models including H1975, BT474, HCT116, H1975 and U87MG [1, 2]
参考文献:
[1] Venkatesan A M, Dehnhardt C M, Delos Santos E, et al. Bis (morpholino-1, 3, 5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. Journal of medicinal chemistry, 2010, 53(6): 2636-2645.
[2] Mallon R, Feldberg L R, Lucas J, et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clinical Cancer Research, 2011, 17(10): 3193-3203.
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Cell experiment: |
Cell proliferation is measured using the MTT dye reduction method. In brief, tumor cells (2×103/100 μL/well) are plated into each well of 96-well plates in RMPI-1640 with 10% FBS and incubated for 24 hours. Culture medium containing several concentrations of GSK2126458 (0-3 μM) or Gedatolisib (PKI-587) (0-3 μM) are added to each well, and the cells are incubated for 24 to 72 hours. Next, 50 μL of MTT (2 mg/mL) is added to each well, and cells are incubated for 2 hours at 37°C. The medium containing MTT solution is removed, and the dark blue crystals are dissolved by adding 100 μL DMSO. The absorbance is measured with a microplate reader at test and reference wavelengths of 550 and 630 nm, respectively. The percentage growth is determined relative to untreated controls. Each experiment is performed at least three times, each with triplicate samples[2]. |
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Animal experiment: |
Mice[2] Suspensions of 5×106/0.2 mL 5-8F cells are injected subcutaneously into the right hindlimbs of 5- to 7-week-old female BALB/c-nu/nu nude mice. When tumor volumes reach 200 mm3, mice are randomly assigned to control and treated groups (5 mice per group). The treated groups receive 300 μg/kg GSK2126458, 25 mg/kg PKI-587, IR, 300 μg/kg GSK2126458 combined with IR, or 25 mg/kg Gedatolisib (PKI-587) combined with IR. GSK2126458 is administered by intragastric administration once daily for 5 consecutive days each week and Gedatolisib (PKI-587) is administered by intravenous injection via tail vein once per 5 days. Mice in the IR groups are irradiated with 2 Gy every other day for four treatments. In combination therapy, GSK2126458 or Gedatolisib (PKI-587) is administered 2 hours before IR exposure. Tumor sizes are calculated every 2 days. Tumor regrowth delay is expressed as the time in days for xenografts treated with GSK2126458, Gedatolisib (PKI-587), or radiation to grow from 200 to 1,000 mm3 in volume minus the time in days for untreated tumors to reach the same size. |
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参考文献: [1]. Venkatesan AM, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010, 53(6), 2636-2645. |
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