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Purity: ≥98%
Gedatolisib (PF-05212384, PKI-587) is a brand-new, extremely powerful dual inhibitor of PI3Kα, PI3Kγ and mTOR that may have anticancer properties. In cell-free assays, it inhibits PI3Kα, PI3Kγ and mTOR with IC50 values of 0.4 nM, 5.4 nM, and 1.6 nM, respectively. By concentrating on phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, it may have anti-cancer effects. The cellular phosphorylation of PI3K/mTOR signaling pathway proteins is inhibited by PF-05212384. It prevents Akt from being phosphorylated along with the Akt effector proteins GSK3 kinase, ENOS, and PRAS 40. Additionally, in a number of xenograft models, including H1975, BT474, HCT116, H1975, and U87MG, PF-05212384 exhibits strong anti-tumor activity.
| Targets |
PI3Kα (IC50 = 0.4 nM); mTOR (IC50 = 1.6 nM); PI3Kγ (IC50 = 5.4 nM)
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|---|---|
| ln 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] In MDA-361 and PC3-MM2 cell lines, PKI-587 inhibits tumor cell growth with an IC50 of 4 nM and 13.1 nM, respectively. This effect is correlated with the suppression of phosphorylation of PI3K/mTOR signaling pathway proteins.[1]
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| ln Vivo |
PKI-587 treatment at 25 mg/kg intravenously results in low plasma clearance (7 (mL/min)/kg), high volume of distribution (7.2 L/kg), and a lengthy (14.4 hours) half-life in nude mice. With a minimum effective dose (MED) of 3 mg/kg and a maximum tolerated single dose (MTD) of 30 mg/kg against MDA-361 tumors, PKI-587 exhibits strong antitumor efficacy in the MDA-361 xenograft model. While PKI-587 at 25 mg/kg for 7 weeks results in 90% survival of the treated group in the H1975 (non-small-cell lung carcinoma, mutant EGFR [L858R, T790M]) xenograft model. [1]
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| Enzyme Assay |
Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. E545K and H1047R human class I PI3K mutants can be generated in Sf9 or bought from Upstate Biotech. Escherichia coli produces GST-GRP1 (murine), which is then isolated using 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).
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| Cell Assay |
Cells are plated in 96-well culture plates at about 3000 cells per well. PKI-587 is added to cells a day after plating. Viable cell densities are assessed three days after PKI-587 treatment by monitoring the metabolic conversion of the dye MTS (by viable cells), a tried-and-true cell proliferation assay. Freshly thawed and mixed MTS and PMS stocks (20:1) are used for each assay. Following this, 20 L of the MTS/PMS mixture is added to 96-well cell plates, and the plates are incubated for 1 to 2 hours in a cell culture incubator.
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| Animal Protocol |
MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
≤30 mg/kg Administered via i.v. |
| References |
| Molecular Formula |
C32H41N9O4
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|---|---|
| Molecular Weight |
615.7258
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| Exact Mass |
615.32815
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| Elemental Analysis |
C, 62.42; H, 6.71; N, 20.47; O, 10.39
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| CAS # |
1197160-78-3
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| Related CAS # |
1197160-78-3
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| Appearance |
white solid powder
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| 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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| InChi Key |
DWZAEMINVBZMHQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H41N9O4/c1-38(2)27-11-13-39(14-12-27)29(42)24-5-9-26(10-6-24)34-32(43)33-25-7-3-23(4-8-25)28-35-30(40-15-19-44-20-16-40)37-31(36-28)41-17-21-45-22-18-41/h3-10,27H,11-22H2,1-2H3,(H2,33,34,43)
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| Chemical Name |
-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
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| Synonyms |
Gedatolisib; PKI-587; PKI587; PKI 587; PF-05212384; PF05212384; PF 05212384; PF5212384; PF 5212384; PF-5212384
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~2 mg/mL (~3.2 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6241 mL | 8.1204 mL | 16.2409 mL | |
| 5 mM | 0.3248 mL | 1.6241 mL | 3.2482 mL | |
| 10 mM | 0.1624 mL | 0.8120 mL | 1.6241 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03911973 | Active Recruiting |
Drug: Gedatolisib Drug: Talazoparib |
TNBC - Triple-Negative Breast Cancer |
Kari Wisinski | April 17, 2019 | Phase 1 Phase 2 |
| NCT02626507 | Active Recruiting |
Drug: Gedatolisib Drug: Faslodex |
Breast Cancer | Hoffman Oncology | January 2016 | Phase 1 |
| NCT05501886 | Recruiting | Drug: Gedatolisib Drug: Alpelisib |
Breast Cancer | Celcuity, Inc. | September 30, 2022 | Phase 3 |
| NCT03243331 | Completed | Drug: Gedatolisib Drug: PTK7-ADC |
Metastatic Breast Cancer Triple Negative Breast Cancer |
Kathy Miller | January 19, 2018 | Phase 1 |
| NCT02684032 | Completed | Drug: Gedatolisib Drug: Palbociclib |
Breast Cancer | Celcuity, Inc. | June 14, 2016 | Phase 1 |
a,bWe treated cell lines with different concentrations of everolimus (RAD001), PKI-587, or vehicle control for 0, 24, 48, and 96 h and assessed cell viability with the WST-1 assay (Roche).Neuroendocrinology.2017;105(1):90-104. |
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