Home PI3K/Akt/mTOR PI3K inhibitor - mTOR inhibitor Gedatolisib (PKI-587) For research use only.

Gedatolisib (PKI-587)

Synonyms: PF-05212384

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.

Gedatolisib (PKI-587) Chemical Structure

Gedatolisib (PKI-587) Chemical Structure

CAS No. 1197160-78-3

Purity & Quality Control

Gedatolisib (PKI-587) Related Products

Signaling Pathway

PI3K Signaling Pathways

PI3K Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MDA-MB-361 cells Cytotoxicity assay Cytotoxicity against human MDA-MB-361 cells, IC50=0.004 μM 20166697
PC3MM2 cells Cytotoxicity assay Cytotoxicity against human PC3MM2 cells, IC50=0.0131 μM 20166697
MDA-MB-361 cells Function assay Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.008 μM 20166697
MDA-MB-361 cells Function assay Inhibition of Akt S473 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.01 μM 20166697
MDA-MB-361 cells Function assay Inhibition of eNOS phosphorylation in human MDA-MB-361 cells by Western blotting 20166697
MDA-MB-361 cells Function assay Inhibition of PARS40 phosphorylation in human MDA-MB-361 cells by Western blotting 20166697
MDA-MB-361 cells Function assay Inhibition of GSK3 kinase phosphorylation in human MDA-MB-361 cells by Western blotting 20166697
MDA-MB-361 cells Function assay Inhibition of mTOR TORC1 kinase activity in human MDA-MB-361 cells assessed as suppression of p70S6K phosphorylation at < 30 nM 20166697
MDA-MB-361 cells Function assay Inhibition of mTOR TORC1 kinase activity in human MDA-MB-361 cells assessed as suppression of 4EBP1 phosphorylation at < 30 nM 20166697
MDA-MB-361 cells Function assay Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells xenografted mouse model upto 36 hrs 20166697
MDA-MB-361 cells Function assay Inhibition of Akt S473 phosphorylation in human MDA-MB-361 cells xenografted mouse model upto 36 hrs 20166697
MDA-MB-361 cells Function assay Induction of PARP cleavage in human MDA-MB-361 cells xenografted mouse model upto 18 hrs 20166697
MDA-MB-361 cells Function assay Antitumor activity against human MDA-MB-361 cells xenografted mouse model assessed as reduction in tumor volume at 20 mg/kg, iv on day 1, 5, 9 20166697
SF9 insect cells Function assay 2 h Inhibition of human PI3Kalpha expressed in SF9 insect cells after 2 hrs by fluorescence polarization assay, IC50=0.0004 μM 21763134
SF9 insect cells Function assay 2 h Inhibition of human PI3Kgamma expressed in SF9 insect cells after 2 hrs by fluorescence polarization assay, IC50=0.011μM 21763134
MDA-MB-361 cells Growth inhibition assay 72 h Growth inhibition of human MDA-MB-361 cells after 72 hrs, IC50=0.003 μM 21763134
human PC3 cells Growth inhibition assay 72 h Growth inhibition of human PC3 cells after 72 hrs, IC50=0.011 μM 21763134
Click to View More Cell Line Experimental Data

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
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]
Kinase Assay 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 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.
Experimental Result Images Methods Biomarkers Images PMID
Growth inhibition assay Cell viability 29978469
Western blot p-AKT / p-mTOR / p-p70S6K / p-S6K / p-4E-BP1 / AKT / mTOR / p70S6K / S6K / 4EBP1 TSC1 / TSC2 / Raptor 29978469
In Vivo
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]
Animal Research Animal Models MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
Dosages ≤30 mg/kg
Administration Administered via i.v.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02438761 Terminated
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
NCT02069158 Completed
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
NCT01420081 Terminated
Endometrial Neoplasms
Pfizer
 January 19 2012 Phase 2

Chemical Information & Solubility

Molecular Weight 615.73 Formula

C32H41N9O4
CAS No. 1197160-78-3 SDF Download Gedatolisib (PKI-587) SDF
Smiles CN(C)C1CCN(CC1)C(=O)C2=CC=C(C=C2)NC(=O)NC3=CC=C(C=C3)C4=NC(=NC(=N4)N5CCOCC5)N6CCOCC6
Storage (From the date of receipt)

In vitro
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DMSO : 3 mg/mL ( (4.87 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 1 mg/mL

Water : Insoluble


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