Gedatolisib (PKI-587)

For research use only.

Catalog No.S2628 Synonyms: PF-05212384

12 publications

Gedatolisib (PKI-587) Chemical Structure

CAS No. 1197160-78-3

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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Selleck's Gedatolisib (PKI-587) has been cited by 12 publications

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 (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 (PKI-587) purchased from Selleck.

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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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MDA-MB-361 cells NYX3ZWpPS3m2b4TvfIlkcXS7IHHzd4F6 NUjIPVVSS3m2b4TvfIlkcXS7IHHnZYlve3RiaIXtZY4hVUSDLV3CMVM3OSClZXzsd{whUUN3ME2wMlAxPCEQvF2= NYTKdWR6OjBzNk[2PVc>
PC3MM2 cells MmnVR5l1d3SxeHnjbZR6KGG|c3H5 NHXTWYdEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBRSzOPTUKgZ4VtdHNuIFnDOVA:OC5yMUOxJO69VQ>? NYnTUZUxOjBzNk[2PVc>
MDA-MB-361 cells MnzRSpVv[3Srb36gZZN{[Xl? NUDtelljUW6qaXLpeIlwdiCxZjDBb5QhXDNyODDwbI9{eGixconsZZRqd25iaX6gbJVu[W5iTVTBMW1DNTN4MTDj[YxteyCkeTDX[ZN1\XKwIHLsc5R1cW6pLDDJR|UxRTBwMEC4JO69VQ>? NHzoU|IzODF4Nk[5Oy=>
MDA-MB-361 cells NVW5TY5NTnWwY4Tpc44h[XO|YYm= NEDTWYpKdmirYnn0bY9vKG:oIFHreEBUPDd|IIDoc5NxcG:{eXzheIlwdiCrbjDoeY1idiCPRFGtUWIuOzZzIHPlcIx{KGK7IGfld5Rmem5iYnzveJRqdmduIFnDOVA:OC5yMTFOwG0> MXGyNFE3PjZ7Nx?=
MDA-MB-361 cells NVTLUIlxTnWwY4Tpc44h[XO|YYm= NFXZdpdKdmirYnn0bY9vKG:oIHXOU3MheGixc4Doc5J6dGG2aX;uJIlvKGi3bXHuJG1FSS2PQj2zOlEh[2WubIOgZpkhX2W|dHXyckBjdG:2dHnu[y=> M3LjZVIxOTZ4Nkm3
MDA-MB-361 cells NIfEfGlHfW6ldHnvckBie3OjeR?= MW\Jcohq[mm2aX;uJI9nKFCDUmO0NEBxcG:|cHjvdplt[XSrb36gbY4hcHWvYX6gUWRCNU2ELUO2NUBk\WyuczDifUBY\XO2ZYLuJIJtd3S2aX7n MkP0NlAyPjZ4OUe=
MDA-MB-361 cells NYe2V3luTnWwY4Tpc44h[XO|YYm= NH\J[I5KdmirYnn0bY9vKG:oIFfTT|Mhc2mwYYPlJJBpd3OyaH;yfYxifGmxbjDpckBpfW2jbjDNSGEuVUJvM{[xJINmdGy|IHL5JHdme3Sncn6gZoxwfHSrbne= NEW1Z4EzODF4Nk[5Oy=>
MDA-MB-361 cells M4jXe2Z2dmO2aX;uJIF{e2G7 MnnzTY5pcWKrdHnvckBw\iCvVF;SJHRQWkNzIHvpcoF{\SCjY4Tpeol1gSCrbjDoeY1idiCPRFGtUWIuOzZzIHPlcIx{KGG|c3Xzd4VlKGG|IIP1dJBz\XO|aX;uJI9nKHB5MGO2T{BxcG:|cHjvdplt[XSrb36gZZQhRCB|MDDuUS=> M2iyRVIxOTZ4Nkm3
MDA-MB-361 cells MYnGeY5kfGmxbjDhd5NigQ>? MY\Jcohq[mm2aX;uJI9nKG2WT2KgWG9TSzFia3nuZZNmKGGldHn2bZR6KGmwIHj1cYFvKE2GQT3NRk0{PjFiY3XscJMh[XO|ZYPz[YQh[XNic4XwdJJme3Orb36gc4YhPEWEUEGgdIhwe3Cqb4L5cIF1cW:wIHH0JFwhOzBibl2= MXeyNFE3PjZ7Nx?=
MDA-MB-361 cells MVrGeY5kfGmxbjDhd5NigQ>? MnXvTY5pcWKrdHnvckBw\iCDa4SgWFMxQCCyaH;zdIhwenmuYYTpc44hcW5iaIXtZY4hVUSDLV3CMVM3OSClZXzsd{B5\W6xZ4Lh[pRm\CCvb4Xz[UBud2SnbDD1dJRwKDN4IHjydy=> M2DtXFIxOTZ4Nkm3
MDA-MB-361 cells NXTLZmh{TnWwY4Tpc44h[XO|YYm= MVvJcohq[mm2aX;uJI9nKEGtdDDTOFc{KHCqb4PwbI9zgWyjdHnvckBqdiCqdX3hckBOTEFvTVKtN|YyKGOnbHzzJJhmdm:pcnHmeIVlKG2xdYPlJI1w\GWuIIXweI8hOzZiaILz M3zENFIxOTZ4Nkm3
MDA-MB-361 cells MmrxSpVv[3Srb36gZZN{[Xl? MWjJcoR2[3Srb36gc4YhWEGUUDDjcIVifmGpZTDpckBpfW2jbjDNSGEuVUJvM{[xJINmdGy|IIjlco9oemGodHXkJI1wfXOnIH3v[IVtKHWydH:gNVghcHK| NI\xclAzODF4Nk[5Oy=>
MDA-MB-361 cells NGPkSZdHfW6ldHnvckBie3OjeR?= NWjDRZZ5SW62aYT1cY9zKGGldHn2bZR6KGGpYXnud5QhcHWvYX6gUWRCNU2ELUO2NUBk\WyuczD4[Y5w\3KjZoTl[EBud3W|ZTDtc4RmdCCjc4Pld5Nm\CCjczDy[YR2[3Srb36gbY4hfHWvb4Kgeo9tfW2nIHH0JFIxKG2pL3vnMEBqfiCxbjDkZZkhOSxiNTygPS=> M2\DbVIxOTZ4Nkm3
SF9 insect cells MoXKSpVv[3Srb36gZZN{[Xl? M2TFV|IhcA>? MX3Jcohq[mm2aX;uJI9nKGi3bXHuJHBKO0ujbIDoZUBmgHC{ZYPz[YQhcW5iU1[5JIlve2WldDDj[YxteyCjZoTldkAzKGi{czDifUBndHWxcnXzZ4Vv[2VicH;sZZJqgmG2aX;uJIF{e2G7LDDJR|UxRTBwMECwOEDPxE1? NV;CTJRnOjF5NkOxN|Q>
SF9 insect cells M4\hPGZ2dmO2aX;uJIF{e2G7 M1jIelIhcA>? NXqyS3BxUW6qaXLpeIlwdiCxZjDoeY1idiCSSUPL[4FudWFiZYjwdoV{e2WmIHnuJHNHQSCrboPlZ5Qh[2WubIOgZYZ1\XJiMjDodpMh[nliZnz1c5Jme2OnbnPlJJBwdGG{aYrheIlwdiCjc4PhfUwhUUN3ME2wMlAyOc7:TR?= M{fncVIyPzZ|MUO0
MDA-MB-361 cells NUjJN41iT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MkGwO|IhcA>? Mm\0S5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gUWRCNU2ELUO2NUBk\WyuczDh[pRmeiB5MjDodpMtKEmFNUC9NE4xODNizszN NUPQUoVyOjF5NkOxN|Q>
human PC3 cells M2K1cWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NXfI[JplPzJiaB?= MnjmS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gVGM{KGOnbHzzJIFnfGW{IEeyJIhzeyxiSVO1NF0xNjBzMTFOwG0> M{nScFIyPzZ|MUO0

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Growth inhibition assay
Cell viability; 

PubMed: 29978469     


A total of 29 CRC cell lines were treated with vehicle or gedatolisib at the indicated concentrations for 72 h, and IC50 values were determined using the MTT viability assay. Untreated cells were considered 100% viable.

29978469
Western blot
p-AKT / p-mTOR / p-p70S6K / p-S6K / p-4E-BP1 / AKT / mTOR / p70S6K / S6K / 4EBP1 ; 

PubMed: 29978469     


CRC cell lines were treated with vehicle or gedatolisib at 1 μM for 24 h, and cell lysates were subjected to western blotting with antibodies specific for total or phosphorylated proteins as indicated

TSC1 / TSC2 / Raptor ; 

PubMed: 29978469     


HCT‐116 (sensitive) and HCT‐15 and LS174T (resistant) cells were treated with vehicle or gedatolisib at 1 μM for 12 h. TSC2 and Raptor were immunoprecipitated from cell lysates and subjected to western blotting with antibodies to TSC1 or TSC2 and mTOR or Raptor (upper rows). 30% of input cell lysate was blotted with antibodies to total or phosphorylated forms of the indicated proteins (lower rows). 

29978469
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]
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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]
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  • Animal Models: MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
  • 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
in solvent
Synonyms PF-05212384
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

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02438761 Terminated Drug: PF-05212384 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 Drug: PF-05212384|Drug: Paclitaxel|Drug: Carboplatin 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 Drug: PF-05212384 Endometrial Neoplasms Pfizer January 19 2012 Phase 2
NCT01347866 Terminated Drug: PF-05212384|Drug: PD-0325901|Drug: irinotecan Advanced Cancer Pfizer October 2011 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID