Gedatolisib (PF-05212384, PKI-587)
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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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.
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|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.|
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.  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. 
|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. |
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).
|In vitro||DMSO||2 mg/mL (3.24 mM)|
* 1 mg/ml means slightly soluble or insoluble.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02438761||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||June 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 2|
|NCT01925274||Terminated||Metastatic Colorectal Cancer||Pfizer||November 2013||Phase 2|
|NCT01920061||Recruiting||Neoplasm||Pfizer||September 2013||Phase 1|
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