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MedKoo Cat#: 406432 | Name: PF-4708671
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

PF-4708671
PF-4708671
CAS#1255517-76-0

Theoretical Analysis

MedKoo Cat#: 406432

Name: PF-4708671

CAS#: 1255517-76-0

Chemical Formula: C19H21F3N6

Exact Mass: 390.1780

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
10mg USD 90.00 Ready to ship
25mg USD 180.00 Ready to ship
50mg USD 300.00 Ready to ship
100mg USD 500.00 Ready to ship
200mg USD 850.00 Ready to ship
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Related CAS #
No Data
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
More Info
 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.       
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/
Solvent mg/mL mM
Solubility
DMSO 20.0 51.20
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.
1: Chi OZ, Liu X, Fortus H, Werlen G, Jacinto E, Weiss HR. Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism- Tuberous Sclerosis. Neuromolecular Med. 2024 Apr 4;26(1):10. doi: 10.1007/s12017-024-08780-7. PMID: 38570425; PMCID: PMC10990997. 2: David J, Mousset M, Trombetti K, Sayasouk B, Neilsen C, Suorsa P, Ruben M, Ruben E, Thiessen J, Pychewicz T, Chu P, Huynh TN. Chronic mild stress leads to anxiety-like behavior and decreased p70 S6K1 activity in the hippocampus of male mice. Physiol Behav. 2024 Jan 1;273:114377. doi: 10.1016/j.physbeh.2023.114377. Epub 2023 Oct 19. PMID: 37863347. 3: Zhang Y, Cheng X, Wu L, Li J, Liu C, Wei M, Zhu C, Huang H, Lin W. Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats. CNS Neurosci Ther. 2024 Mar;30(3):e14475. doi: 10.1111/cns.14475. Epub 2023 Sep 22. PMID: 37736829; PMCID: PMC10945394. 4: Zhang H, Zhang HR, Zhang J, Hu ML, Ren L, Luo QQ, Qi HZ. Discovery of novel S6K1 inhibitors by an ensemble-based virtual screening method and molecular dynamics simulation. J Mol Model. 2023 Mar 18;29(4):102. doi: 10.1007/s00894-023-05504-9. PMID: 36933164. 5: Luo K, Liu S, Shen X, Xu J, Shi C, Chao Y, Wen Z, Zhang K, Wang R, Liu B, Jiang Y. Integration of cancer stemness and neoantigen load to predict responsiveness to anti-PD1/PDL1 therapy. Front Cell Dev Biol. 2022 Nov 17;10:1003656. doi: 10.3389/fcell.2022.1003656. PMID: 36467413; PMCID: PMC9714307. 6: Shi X, von Weltin E, Fitzsimmons E, Do C, Caban Rivera C, Chen C, Liu-Chen LY, Unterwald EM. Reactivation of cocaine contextual memory engages mechanistic target of rapamycin/S6 kinase 1 signaling. Front Pharmacol. 2022 Sep 27;13:976932. doi: 10.3389/fphar.2022.976932. PMID: 36238569; PMCID: PMC9552424. 7: Kim G, Jang SK, Kim YJ, Jin HO, Bae S, Hong J, Park IC, Lee JH. Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway. Int J Mol Sci. 2022 Aug 6;23(15):8761. doi: 10.3390/ijms23158761. PMID: 35955892; PMCID: PMC9369036. 8: Nishimura Y, Chunthorng-Orn J, Lord S, Musa I, Dawson P, Holm L, Lai YC. Ubiquitin E3 ligase Atrogin-1 protein is regulated via the rapamycin-sensitive mTOR-S6K1 signaling pathway in C2C12 muscle cells. Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C215-C225. doi: 10.1152/ajpcell.00384.2021. Epub 2022 Jun 15. PMID: 35704697. 9: Huang B, Hao M, Li C, Luo KQ. Acetyltanshinone IIA reduces the synthesis of cell cycle-related proteins by degrading p70S6K and subsequently inhibits drug- resistant lung cancer cell growth. Pharmacol Res. 2022 May;179:106209. doi: 10.1016/j.phrs.2022.106209. Epub 2022 Apr 6. PMID: 35398238. 10: Spaan I, Timmerman LM, Kimman T, Slomp A, Cuenca M, van Nieuwenhuijzen N, Moesbergen LM, Minnema MC, Raymakers RA, Peperzak V. Direct P70S6K1 inhibition to replace dexamethasone in synergistic combination with MCL-1 inhibition in multiple myeloma. Blood Adv. 2021 Jun 22;5(12):2593-2607. doi: 10.1182/bloodadvances.2020003624. PMID: 34152396; PMCID: PMC8270664. 11: Raj N, McEachin ZT, Harousseau W, Zhou Y, Zhang F, Merritt-Garza ME, Taliaferro JM, Kalinowska M, Marro SG, Hales CM, Berry-Kravis E, Wolf-Ochoa MW, Martinez-Cerdeño V, Wernig M, Chen L, Klann E, Warren ST, Jin P, Wen Z, Bassell GJ. Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis. Cell Rep. 2021 Apr 13;35(2):108991. doi: 10.1016/j.celrep.2021.108991. PMID: 33852833; PMCID: PMC8133829. 12: Li Y, Yi L, Cheng S, Wang Y, Wang J, Sun J, Zhang Q, Xu X. Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide. J Gen Virol. 2021 Mar;102(3). doi: 10.1099/jgv.0.001534. Epub 2021 Jan 8. PMID: 33416466. 13: Wang J, Prinz RA, Liu X, Xu X. In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2. Viruses. 2020 Oct 8;12(10):1141. doi: 10.3390/v12101141. PMID: 33050000; PMCID: PMC7650803. 14: 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. 15: Chi OZ, Mellender SJ, Kiss GK, Chiricolo A, Liu X, Patel N, Jacinto E, Weiss HR. Lysophosphatidic acid increased infarct size in the early stage of cerebral ischemia-reperfusion with increased BBB permeability. J Stroke Cerebrovasc Dis. 2020 Oct;29(10):105029. doi: 10.1016/j.jstrokecerebrovasdis.2020.105029. Epub 2020 Jul 15. PMID: 32912542. 16: MacCallum PE, Blundell J. The mTORC1 inhibitor rapamycin and the mTORC1/2 inhibitor AZD2014 impair the consolidation and persistence of contextual fear memory. Psychopharmacology (Berl). 2020 Sep;237(9):2795-2808. doi: 10.1007/s00213-020-05573-1. Epub 2020 Jun 29. PMID: 32601986. 17: Zhang N, Ma S. Research Progress of 70 kDa Ribosomal Protein S6 Kinase (P70S6K) Inhibitors as Effective Therapeutic Tools for Obesity, Type II Diabetes and Cancer. Curr Med Chem. 2020;27(28):4699-4719. doi: 10.2174/0929867327666200114113139. PMID: 31942845. 18: 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. 19: Abe K, Yano T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibata S, Igaki Y, Ino S, Miura T. mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation. Biochim Biophys Acta Mol Basis Dis. 2019 Dec 1;1865(12):165552. doi: 10.1016/j.bbadis.2019.165552. Epub 2019 Sep 6. PMID: 31499159. 20: Weiss HR, Mellender SJ, Kiss GK, Liu X, Chi OZ. Improvement in Microregional Oxygen Supply/Consumption Balance and Infarct Size After Cerebral Ischemia- Reperfusion With Inhibition of p70 Ribosomal S6 Kinase (S6K1). J Stroke Cerebrovasc Dis. 2019 Oct;28(10):104276. doi: 10.1016/j.jstrokecerebrovasdis.2019.06.034. Epub 2019 Jul 23. PMID: 31350168.