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Purity: =99.29%
PF-4708671 is a novel, potent, highly specific and cell-permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform)/RSK1 with potential antitumor activity. In cell-free assays, it inhibits RSK1 with a Ki/IC50 of 20 nM/160 nM, shows 400-fold greater selectivity for S6K1 over S6K2, and exhibits 4- and >20-fold selectivity for S6K1 over MSK1 and RSK1/2, respectively. As the first S6K1-specific inhibitor reported, PF-4708671 showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo by preventing the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases.
| Targets |
S6K1 (IC50 = 160 nM); S6K1 (Ki = 20 nM); S6K2 (IC50 = 65 μM)
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|---|---|
| ln Vitro |
PF-4708671 inhibits the activity of full-length S6K1 in vitro with a Ki of 20 nM, and S6K1 isolated from IGF1-stimulated HEK293 cells with an IC50 of 0.16 μM, and only very slightly (IC50 of 65 μM) inhibits the closely related S6K2 isoform. Over 20 times less potently than S6K1, PF-4708671 inhibits RSK1 (IC50 of 4.7 μM) and RSK2 (IC50 of 9.2 μM). PF4708671 inhibits MSK1 four times less potently than S6K1 (IC50 = 0.95 μM)[1]. HCT116 cells are treated with (i) vehicle (DMSO), (ii) OSI-906 (5 μM), (iii) PF-4708671 (10 μM), and (iv) OSI-906 (5 μM)+PF-4708671 (10 μM) for various amounts of time. OSI-906 alone (closed square) or PF4708671 alone (open circle) treatments on HCT116 cells marginally inhibit cell growth. The combination of OSI-906 and PF-4708671, on the other hand, significantly reduces HCT116 cell proliferation after a 2-day treatment (closed circle). When SW480 cells are treated with the mixture of OSI-906 and PF-4708671, the outcome is also similar. In comparison to vehicle, OSI-906 alone, or PF-4708671 alone treated HCT116 or SW480 cells, colony formation is also significantly decreased in OSI-906+PF-4708671-treated cells[2].
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| ln Vivo |
The tumor growth rate in mice treated with the combination of OSI-906+PF-4708671 is significantly slower than that of OSI-906 alone (P=0.0189) or PF4708671 alone (P=0.0165) treated mice. At the conclusion of a 15-day treatment period, the average tumor volume in OSI-906+PF-4708671-treated mice is approximately 50% smaller than that in mice treated with OSI-906 (P=0.0056) or PF-4708671 alone (P<0.001)[2].
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| Enzyme Assay |
PF-4708671 is a cell-permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform) with Ki/IC50 of 20 nM/160 nM in cell-free assays, 400-fold greater selectivity for S6K1 than S6K2, and 4- and >20-fold selectivity for S6K1 than MSK1 and RSK1/2, respectively.
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| Cell Assay |
These cells include GEO, HT29, SW480, and HCT116. XTT and clonogenic assays are used to determine how OSI-906 or OSI-906 and PF-4708671 affect cell proliferation. Cell Proliferation Kit II (XTT) is used to carry out XTT assays. For clonogenic assays, cells (1 103 cells/well) are seeded on a 6-well plate and then given drug treatments (OSI-906 5 M, PF-4708671 10 M). Cells are stained with 1% crystal violet after one week of incubation, and the number of colonies is counted and noted[2].
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| Animal Protocol |
Mice: The following groups (five mice/group) of female athymic nude mice (Hsd:Athymic Nude-Foxn1nu) are randomly assigned. Mice are given either OSI-906 (30 mg/kg) or vehicle (25 mM tartaric acid) for 12 days prior to the injection of HT29-L and HT29-P cells. Mice are administered the following drugs orally for 14 days prior to the injection of HCT116 cells: vehicle (25 mM tartaric acid); OSI-906 alone (30 mg/kg); PF-4708671 alone (60 mg/kg); and OSI-906 (30 mg/kg)+PF-4708671 (60 mg/kg). Each day, one dose of OSI-906, one dose of PF-4708671, and one dose of Vehicle are administered. The mice are sacrificed, and the weights of the tumors were measured, twenty-four hours after the last treatment[2].
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| References |
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| Molecular Formula |
C19H21N6F3
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|---|---|
| Molecular Weight |
390.40544
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| Exact Mass |
390.17798
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| Elemental Analysis |
C, 58.45; H, 5.42; F, 14.60; N, 21.53
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| CAS # |
1255517-76-0
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| Related CAS # |
1255517-76-0
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| Appearance |
solid powder
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| SMILES |
FC(C1=CC=C2NC(CN3CCN(C4=NC=NC=C4CC)CC3)=NC2=C1)(F)F
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| InChi Key |
FBLPQCAQRNSVHB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21F3N6/c1-2-13-10-23-12-24-18(13)28-7-5-27(6-8-28)11-17-25-15-4-3-14(19(20,21)22)9-16(15)26-17/h3-4,9-10,12H,2,5-8,11H2,1H3,(H,25,26)
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| Chemical Name |
2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole
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| Synonyms |
PF-4708671; PF4708671; PF 4708671
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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: ~30 mg/mL (76.8 mM)
Water: <1 mg/mL Ethanol: 8 mg/mL (20.5 mM) |
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| Solubility (In Vivo) |
30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5614 mL | 12.8070 mL | 25.6141 mL | |
| 5 mM | 0.5123 mL | 2.5614 mL | 5.1228 mL | |
| 10 mM | 0.2561 mL | 1.2807 mL | 2.5614 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.
Pdcd4 enhances cell sensitivity to OSI-906 via suppression of p70S6K1 phosphorylation.Mol Cancer Ther.2015 Mar;14(3):799-809. |
The combination of OSI-906 and PF-4708671 significantly inhibits the growth of resistant CRC cells.Mol Cancer Ther.2015 Mar;14(3):799-809. |
The combination of OSI-906 and PF-4708671 significantly inhibits the growth of HCT116-derived tumor in nude mice.Mol Cancer Ther.2015 Mar;14(3):799-809. |
Expression level of Pdcd4 correlates with cell sensitivity to OSI-906.Mol Cancer Ther.2015 Mar;14(3):799-809. |
Tumors derived from Pdcd4 knockdown cells resist to OSI-906 treatment.Mol Cancer Ther.2015 Mar;14(3):799-809. |
Knockdown of p70S6K1 but not p70S6K2 enhances cell sensitivity to OSI-906.Mol Cancer Ther.2015 Mar;14(3):799-809. |
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