PF-4708671
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MedKoo CAT#: 406432

CAS#: 1255517-76-0

Description: PF-4708671 is a novel cell-permeable inhibitor of S6K1. PF-4708671 specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents 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.


Chemical Structure

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PF-4708671
CAS# 1255517-76-0

Theoretical Analysis

MedKoo Cat#: 406432
Name: PF-4708671
CAS#: 1255517-76-0
Chemical Formula: C19H21F3N6
Exact Mass: 390.17798
Molecular Weight: 390.41
Elemental Analysis: C, 58.45; H, 5.42; F, 14.60; N, 21.53

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 190.0 Ready to ship
50.0mg USD 350.0 Ready to ship
100.0mg USD 550.0 Ready to ship
200.0mg USD 950.0 Ready to ship
500.0mg USD 1950.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5250.0 2 Weeks
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Synonym: PF4708671; PF-4708671; PF 4708671.

IUPAC/Chemical Name: 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole

InChi Key: FBLPQCAQRNSVHB-UHFFFAOYSA-N

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)

SMILES Code: FC(C1=CC=C2NC(CN3CCN(C4=NC=NC=C4CC)CC3)=NC2=C1)(F)F

Appearance: solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble to 50 mM in DMSO and to 50 mM in ethanol, not soluble in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in ethanol: PF-4708671 was dissolved in ethanol and subsequently diluted in soya bean oil. (see Biochem J. 2012 Jan 1;441(1):199-207.)

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: PF-4708671 is a potent cell-permeable S6K1 inhibitor with a Ki of 20 nM and IC50 of 160 nM.
In vitro activity: To determine whether PF-4708671 can synergistically enhance the cytotoxicity of TKI in resistant cells, a MTT assay was used to examine the effects of PF and TKI on cell viabilities. More than 60% cells were still viable when treated with osimertinib or PF alone at the highest doses (Fig.5B, C). Notably, the combination of osimertinib and PF induced higher cytotoxicity in HCC827-OR cells (Fig.5D). The combination index (CI) analyzed by CompuSyn software showed the strong synergism between osimertinib and PF (Fig. 5E). Similar results were obtained in PC-9/G cells treated with gefitinib (Fig.S4D, E, F, G), indicating that PF-4708671 was able to re-sensitize resistant cells to TKI. Reference: Oncogene. 2020 Dec; 39(49): 7181–7195. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718330/
In vivo activity: This study used differentiated muscle cells from WT mice or mice lacking both AMPKα1 and AMPKα2 catalytic subunits (AMPK α1/2 dKO muscle cells). After 5 and 48 h of treatment with PF (PF-4708671), AMPK phosphorylation on Thr-172 and ACC phosphorylation on Ser-79 were increased in differentiated WT myocytes but, as expected, not in AMPK α1/2 dKO muscle cells (Fig. 2A). In both AMPK WT and dKO muscle cells, PF treatment decreased basal and insulin-stimulated S6 phosphorylation in both WT and AMPK α1/2 dKO muscle cells. PF treatment of both WT and AMPK α1/2 dKO muscle cells for 5 and 48 h increased glucose uptake compared with vehicle-treated cells (Fig. 2B). However, lack of AMPK activation did not reduce the stimulatory effects of PF treatment on muscle glucose uptake. These data demonstrate that AMPK is dispensable for the stimulatory effect of PF on muscle glucose uptake. Reference: J Biol Chem. 2019 Aug 9; 294(32): 12250–12260. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690709/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 20.0 51.2

Preparing Stock Solutions

The following data is based on the product molecular weight 390.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Shen H, Wang GC, Li X, Ge X, Wang M, Shi ZM, Bhardwaj V, Wang ZX, Zinner RG, Peiper SC, Aplin AE, Jiang BH, He J. S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Oncogene. 2020 Dec;39(49):7181-7195. doi: 10.1038/s41388-020-01497-4. Epub 2020 Oct 9. PMID: 33037411; PMCID: PMC7718330. 2. Archambault AS, Turcotte C, Martin C, Lefebvre JS, Provost V, Laviolette M, Flamand N. Leukotriene B₄ Metabolism and p70S6 Kinase 1 Inhibitors: PF-4708671 but Not LY2584702 Inhibits CYP4F3A and the ω-Oxidation of Leukotriene B₄ In Vitro and In Cellulo. PLoS One. 2017 Jan 9;12(1):e0169804. doi: 10.1371/journal.pone.0169804. PMID: 28068410; PMCID: PMC5222342. 3. Kam K, Kang M, Eren CY, Pettibone WD, Bowling H, Taveras S, Ly A, Chen RK, Berryman NV, Klann E, Varga AW. Interactions between sleep disruption, motor learning, and p70 S6 kinase 1 signaling. Sleep. 2020 Mar 12;43(3):zsz244. doi: 10.1093/sleep/zsz244. PMID: 31608388; PMCID: PMC7315768. 4. Shum M, Houde VP, Bellemare V, Junges Moreira R, Bellmann K, St-Pierre P, Viollet B, Foretz M, Marette A. Inhibition of mitochondrial complex 1 by the S6K1 inhibitor PF-4708671 partly contributes to its glucose metabolic effects in muscle and liver cells. J Biol Chem. 2019 Aug 9;294(32):12250-12260. doi: 10.1074/jbc.RA119.008488. Epub 2019 Jun 26. PMID: 31243102; PMCID: PMC6690709.
In vitro protocol: 1. Shen H, Wang GC, Li X, Ge X, Wang M, Shi ZM, Bhardwaj V, Wang ZX, Zinner RG, Peiper SC, Aplin AE, Jiang BH, He J. S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Oncogene. 2020 Dec;39(49):7181-7195. doi: 10.1038/s41388-020-01497-4. Epub 2020 Oct 9. PMID: 33037411; PMCID: PMC7718330. 2. Archambault AS, Turcotte C, Martin C, Lefebvre JS, Provost V, Laviolette M, Flamand N. Leukotriene B₄ Metabolism and p70S6 Kinase 1 Inhibitors: PF-4708671 but Not LY2584702 Inhibits CYP4F3A and the ω-Oxidation of Leukotriene B₄ In Vitro and In Cellulo. PLoS One. 2017 Jan 9;12(1):e0169804. doi: 10.1371/journal.pone.0169804. PMID: 28068410; PMCID: PMC5222342.
In vivo protocol: 1. Kam K, Kang M, Eren CY, Pettibone WD, Bowling H, Taveras S, Ly A, Chen RK, Berryman NV, Klann E, Varga AW. Interactions between sleep disruption, motor learning, and p70 S6 kinase 1 signaling. Sleep. 2020 Mar 12;43(3):zsz244. doi: 10.1093/sleep/zsz244. PMID: 31608388; PMCID: PMC7315768. 2. Shum M, Houde VP, Bellemare V, Junges Moreira R, Bellmann K, St-Pierre P, Viollet B, Foretz M, Marette A. Inhibition of mitochondrial complex 1 by the S6K1 inhibitor PF-4708671 partly contributes to its glucose metabolic effects in muscle and liver cells. J Biol Chem. 2019 Aug 9;294(32):12250-12260. doi: 10.1074/jbc.RA119.008488. Epub 2019 Jun 26. PMID: 31243102; PMCID: PMC6690709.

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1: Leontieva OV, Demidenko ZN, Blagosklonny MV. S6K in geroconversion. Cell Cycle. 2013 Oct 15;12(20):3249-52. doi: 10.4161/cc.26248. Epub 2013 Sep 9. PubMed PMID: 24036549.

2: Allard EK, Grujic M, Fisone G, Kristensson K. Prion formation correlates with activation of translation-regulating protein 4E-BP and neuronal transcription factor Elk1. Neurobiol Dis. 2013 Oct;58:116-22. doi: 10.1016/j.nbd.2013.05.014. Epub 2013 Jun 3. PubMed PMID: 23742760.

3: Parker WE, Orlova KA, Parker WH, Birnbaum JF, Krymskaya VP, Goncharov DA, Baybis M, Helfferich J, Okochi K, Strauss KA, Crino PB. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013 Apr 24;5(182):182ra53. doi: 10.1126/scitranslmed.3005271. PubMed PMID: 23616120; PubMed Central PMCID: PMC3720125.

4: Rajan MR, Fagerholm S, Jönsson C, Kjølhede P, Turkina MV, Strålfors P. Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. PLoS One. 2013;8(4):e59725. doi: 10.1371/journal.pone.0059725. Epub 2013 Apr 2. PubMed PMID: 23565163; PubMed Central PMCID: PMC3614923.

5: Choi HN, Jin HO, Kim JH, Hong SE, Kim HA, Kim EK, Lee JK, Park IC, Noh WC. 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 Mar 1;432(1):123-8. doi: 10.1016/j.bbrc.2013.01.074. Epub 2013 Jan 29. PubMed PMID: 23376066.

6: Di R, Wu X, Chang Z, Zhao X, Feng Q, Lu S, Luan Q, Hemmings BA, Li X, Yang Z. S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt. Biochem J. 2012 Jan 1;441(1):199-207. doi: 10.1042/BJ20110033. PubMed PMID: 21906027.

7: Rosner M, Schipany K, Hengstschläger M. p70 S6K1 nuclear localization depends on its mTOR-mediated phosphorylation at T389, but not on its kinase activity towards S6. Amino Acids. 2012 Jun;42(6):2251-6. doi: 10.1007/s00726-011-0965-4. Epub 2011 Jun 28. PubMed PMID: 21710263.

8: Bilanges B, Vanhaesebroeck B. A new tool to dissect the function of p70 S6 kinase. Biochem J. 2010 Oct 15;431(2):e1-3. doi: 10.1042/BJ20101445. PubMed PMID: 20874709.

9: Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J, Hwang C, Alessi DR. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010 Oct 15;431(2):245-55. doi: 10.1042/BJ20101024. PubMed PMID: 20704563.



Additional Information

 S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance.