PF-4708671 |
| رقم الكتالوجGC10689 |
PF-4708671 هو مثبط S6K1 فعال للخلايا مع Ki من 20 نانومتر و IC50 من 160 نانومتر
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1255517-76-0
Sample solution is provided at 25 µL, 10mM.
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PF-4708671, is a novel cell-permeable inhibitor of S6K1, specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. [1].
PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1) [1]. RSK1, RSK2 and MSK1 were the other kinases inhibited by PF-4708671 (IC50 = 4.7 µM, 9.2 µM and 0.95 µM, respectively). PF-4708671 decreased phosphorylation of ribosomal protein S6 in HEK-293 cells. PF-4708671 has been used as the standard S6K1 inhibitor for the investigation of the role of S6K1 in several cancers. PF-4708671 in combination with tamoxifen was shown to be highly effective against ER+ MCF7 cells that had overexpression of S6K1 [2] and enhanced cell death in glucose-starved MCF7 cells via downregulation of anti-apoptotic proteins Mcl-1 and survivin [3].
PF-4708671 inhibite the AKT/mTOR/S6K1 pathway led to the inhibition of cell migration in triple-negative MDA-MB-231 cells and inhibition of local relapse in mice models [4]. Moreover, PF-4708671 improved glucose tolerance in high-fat -fed obese mice by restoring Akt S473 phosphorylation in metabolic tissues [5]. PF-4708671 has protective effects against NMDA-induced retinal neurotoxicity in rats [6].
References:
[1]. Pearce, L. R. et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem. J. 431, 245-255 (2010).
[2]. Hong SE, Kim EK, Jin HO, Kim HA, Lee JK, Koh JS, et al. S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell Biol Toxicol. 2013;29(4):273-82.
[3]. Choi HN, Jin HO, Kim JH, Hong SE, Kim HA, Kim EK, et al. Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2013;432(1):123-8.
[4]. Segatto I, Berton S, Sonego M, Massarut S, D'Andrea S, Perin T, et al. Inhibition of breast cancer local relapse by targeting p70S6 kinase activity. J Mol Cell Biol. 2013;5(6):428-31.
[5]. M. Shum, K. Bellmann, P. St-Pierre, A. Marette. Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice .Diabetologia, 59 (2016), pp. 592-603
[6]. Hayashi, I.; Aoki, Y.; Ushikubo, H.; Asano, D.; Mori, A.; Sakamoto, K.; Nakahara, T.; Ishii, K. Protective effects of PF-4708671 againstN-methyl-d-aspartic acid-induced retinal damage in rats. Fundam. Clin. Pharmacol. 2016, 30, 529-536.
| Cell experiment [1]: | |
|
Cell lines |
A549 (adenocarcinoma), NCI-H460 (large cell carcinoma), and SK-MES-1 (squamous cell carcinoma) cells |
|
Preparation Method |
Tumor cells were seeded in 96-well plates at a density of 5×103 per well. After incubation in presence of PF-4708671 (0.1µM, 0.3µM, 1µM, 3µM and 10µM) for 24, 48 and 72 hours, respectively, |
|
Reaction Conditions |
0.1µM, 0.3µM, 1µM, 3µM and 10µM for 24, 48 and 72 hours |
|
Applications |
Proliferation abilities of the three NSCLC cell lines were significantly inhibited by PF-4708671. After 24 hours of treatment, PF-4708671 inhibited H460 cell proliferation at 10µM, and A549 and SK-MES-1 cell amounts were significantly reduced at 3µM and 0.1µM, respectively. In addition, H460, A549, and SK-MES-1 cell growth rates were significantly inhibited by PF-4708671 at 0.3µM, 0.1µM, and 0.1µM, respectively, 48 hours post treatment. All cell lines showed significantly reduced proliferation at 72 hour after treatment with 0.1µM PF-4708671. |
| Animal experiment [2]: | |
|
Animal models |
Male C57Bl/6 mice (6 weeks old) |
|
Preparation Method |
Mice were randomly assigned to three groups: (1) control (HF) receiving vehicle (8% EtOH [vol./vol.], 0.2% [wt/vol.] carboxymethylcellulose sterile); (2) treated with PF-4708671 (35 mg kg-1 day-1, i.p.); or (3) treated with rapamycin (2 mg kg-1 day-1, i.p.) for 7 days while being kept on the same high-fat diet. |
|
Dosage form |
Intraperitoneal injection, 35 mg kg-1 day-1 for 7 days. |
|
Applications |
PF-4708671 did not affect body weight or adiposity, 1 week of PF-4708671 treatment was found to improve fasting glucose whereas rapamycin further increased fasting hyperglycaemia in obese mice. |
|
References: [1]: Qiu ZX, Sun RF, Mo XM and Li WM: The p70S6K specific inhibitor PF-4708671 impedes non-small cell lung cancer growth. PLoS One. 11:e01471852016. |
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| Cas No. | 1255517-76-0 | SDF | |
| Chemical Name | 2-[[4-(5-ethylpyrimidin-4-yl)piperazin-1-yl]methyl]-6-(trifluoromethyl)-1H-benzimidazole | ||
| Canonical SMILES | CCC1=CN=CN=C1N2CCN(CC2)CC3=NC4=C(N3)C=C(C=C4)C(F)(F)F | ||
| Formula | C19H21F3N6 | M.Wt | 390.41 |
| الذوبان | ≥ 19.5mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.5614 mL | 12.807 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 |
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- Purity: >99.50%
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