Gedatolisib (PF-05212384, PKI-587)

Catalog No.S2628

Gedatolisib (PF-05212384, PKI-587) Chemical Structure

Molecular Weight(MW): 615.73

Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM in cell-free assays, respectively. Phase 2.

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2 Customer Reviews

  • PI3K inhibitors promote apoptosis in checkpoint-defective cell lines. Two checkpoint-functional (A2058, D28) and three defective (HT144, D20, SKMel13) melanoma cell lines growth as tumour spheres as in Figure 4B were either untreated or treated with 5 uM PF-05212384 for 72 h, harvested and immunoblotted for pAkt Ser473.

    Pigment Cell Melanoma Res 2014 27(5), 813-21. Gedatolisib (PF-05212384, PKI-587) purchased from Selleck.

    After starved in serum-free medium for 24h,A549 cells incubated with the indicated concentrations of PKI-587 for 3h,followed by 20-minute stimolation of 100ng/ml EGF.

    Dr. Zhang of Tianjin Medical University. Gedatolisib (PF-05212384, PKI-587) purchased from Selleck.

Purity & Quality Control

Choose Selective PI3K Inhibitors

Biological Activity

Description Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM in cell-free assays, respectively. Phase 2.
Targets
PI3Kα [1]
(Cell-free assay)
mTOR [1]
(Cell-free assay)
PI3Kγ [1]
(Cell-free assay)
0.4 nM 1.6 nM 5.4 nM
In vitro

PKI-587 shows potent inhibitory activity against PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. Furthermore, PKI-587 also exhibits its potency against the most frequently occurring mutant forms of PI3Kα, notably the H1047R and E545K with IC50 of 0.6 nM and 0.6 nM, respectively. [1] Correlated with suppression of phosphorylation of PI3K/mTOR signaling pathway proteins, PKI-587 causes tumor cell growth inhibition in MDA-361 and PC3-MM2 cell lines with IC50 of 4 nM and 13.1 nM, respectively. [1]

In vivo In nude mice, PKI-587 treatment at 25 mg/kg iv leads to low plasma clearance (7 (mL/min)/kg), high volume of distribution (7.2 L/kg), and long half-life, (14.4 hours). In the MDA-361 xenograft model, PKI-587 produces potent antitumor efficacy with the minimum efficacious dose (MED) of 3 mg/kg against MDA-361 tumors and maximum tolerated single dose (MTD) of 30 mg/kg. While in the H1975 (non-small-cell lung carcinoma, mutant EGFR [L858R, T790M]) xenograft model, PKI-587 at 25 mg/kg for 7 weeks results in 90% survival of the group treated. [1]

Protocol

Kinase Assay:[1]
+ Expand

PI3K and mTOR kinase assay :

Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. Human class I PI3Ks and PI3K-α mutants (E545K and H1047R) are produced in Sf9 or purchased from Upstate Biotech. GST-GRP1 (murine) is produced in Escherichia coli and isolated by GST-Sepharose. Assay buffers are reaction buffer [20 mM HEPES (pH 7.1), 2 mM MgCl2, 0.05% CHAPS, and 0.01% β-mercaptoethanol] and stop/detection buffer [100 mM HEPES (pH 7.5), 4 mM EDTA, 0.05% CHAPS]. FP reaction is run for 30 minutes at room temperature in 20 μL of reaction buffer containing 20 μM phosphatidylinositol 4,5-bisphosphate (PIP2), 25 μM ATP, and <4% DMSO. FP reaction is stopped with 20 μL of stop/detection buffer (10 nM probe and 40 nM GST-GRP), and after 2 hours, data are collected using an Envision plate reader. The routine assays with purified FLAG-TOR (FL and 3.5) are performed in 96-well plates as follows. Enzymes are first diluted in kinase assay buffer (10 mM Hepes (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl2, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethyl sulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1–6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA).
Cell Research:[1]
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  • Cell lines: MDA-361 and PC3-MM2
  • Concentrations: 0-10 μM
  • Incubation Time: 72 hours
  • Method: Cells are plated in 96-well culture plates at about 3000 cells per well. One day following plating, PKI-587 is added to cells. Three days after PKI-587 treatment, viable cell densities are determined by measuring metabolic conversion (by viable cells) of the dye MTS, a previously established cell proliferation assay. For each assay, MTS and PMS stocks are freshly thawed and mixed (MTS/PMS, 20:1). The MTS/PMS mixture is then added to 96-well cell plates at 20 μL/well, and plates are incubated for 1 hour–2 hours in cell culture incubator. MTS assay results are read in a 96-well format plate reader by measuring absorbance at 490 nm. The effect of each PKI-587 treatment is calculated as a percentage of control cell growth obtained from vehicle-treated cells grown in the same culture plate.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
  • Formulation: Dissolved in 5% dextrose [D5/W], 0.3% lactic acid.
  • Dosages: ≤30 mg/kg
  • Administration: Administered via i.v.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 2 mg/mL (3.24 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 615.73
Formula

C32H41N9O4

CAS No. 1197160-78-3
Storage powder
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02438761 Active, not recruiting Therapy-related Acute Myeloid Leukemia and Myelodysplastic Syndrome|Acute Myeloid Leukemia, in Relapse|de Novo Acute Myeloid Leukemia at Diagnostic Institut Curie|Fondation ARC|National Cancer Institute, France August 31, 2015 Phase 2
NCT02142920 Completed Healthy Pfizer July 2014 Phase 1
NCT02069158 Recruiting Breast Cancer|NSCLC|Ovary Cancer|Endometrial Cancer|Small Cell Lung Cancer (SCLC)|Head and Neck (HNSCC) Cristiana Sessa|Oncology Institute of Southern Switzerland April 2014 Phase 1
NCT01937715 Terminated Metastatic Colorectal Carcinoma Pfizer February 2014 Phase 1|Phase 2
NCT01925274 Terminated Metastatic Colorectal Cancer Pfizer November 2013 Phase 2
NCT01920061 Recruiting Neoplasm Pfizer September 2013 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID