Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)

Pearce, Laura R.; Alton, Gordon; Richter, Daniel; Kath, John C.; Lingardo, Laura; Chapman, Justin; Hwang, Catherine J.; Alessi, Dario R.

doi:10.1042/bj20101024

Cited by 238 publications

(232 citation statements)

References 42 publications

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“…This is consistent with the inhibition of S6K1 by PF-4708671, as seen in vitro (Fig. 1) and previous reports [21,26], suggesting that other kinases might phosphorylate ribosomal S6 proteins in those tissues in vivo.…”

Section: S6k1 Inhibition Increases Glucose Uptake In L6 Myocytessupporting

confidence: 93%

“…1). Moreover, S6K1 Thr389 phosphorylation increased after PF-4708671 treatment, a finding that is in line with previous reports, and that was suggested to involve some feedback pathways by which S6K1 might regulate its own phosphorylation by mTORC1 [21,26]. As previously shown using genetic tools in cells [10], pharmacological S6K1 inhibition by PF-4708671 reduced insulin-stimulated IRS1 S1101 phosphorylation.…”

Section: S6k1 Inhibition Decreases S6 Phosphorylation and Increases Asupporting

confidence: 91%

“…We also ruled out that PF-4708671 might inhibit mitogen and stress activated kinase 1 (MSK1) since this inhibitor did not inhibit Thr581 MSK1 and Ser133 cAMP response element-binding protein (CREB) induced by phorbol myristate acetate (PMA) in hepatocytes (ESM Fig. 1), in line with previous work by Pearce et al [21].…”

Section: S6k1 Inhibition Decreases S6 Phosphorylation and Increases Asupporting

confidence: 85%

“…Vehicle (dimethyl sulfoxide, DMSO 0.02% [vol./vol.]) or rapamycin (25 nmol/l) or PF-4708671 (10 μmol/l) were used since p70 S6 kinase is fully inhibited at this dose [21]. Only mycoplasma free cells were used.…”

Section: Methodsmentioning

confidence: 99%

“…However, no studies have yet evaluated the effect of specifically inhibiting S6K1 on cellular insulin signalling, glucose metabolism and whole-body glucose homeostasis. Recently, the selective S6K1 inhibitor-PF-4708671-has been characterised [21], allowing us to test the effect of pharmacological inhibition of S6K1 on glucose metabolism for the first time. Here, we observed that PF-4708671 reduced hepatic glucose production and stimulated muscle glucose uptake in vitro, in association with increased Akt phosphorylation in both hepatocytes and myocytes.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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Section: S6k1 Inhibition Increases Glucose Uptake In L6 Myocytessupporting

confidence: 93%

Section: S6k1 Inhibition Decreases S6 Phosphorylation and Increases Asupporting

confidence: 91%

Section: S6k1 Inhibition Decreases S6 Phosphorylation and Increases Asupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

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Back in Person: Frontiers in Medicinal Chemistry 2023

Gehringer,

Pape,

Méndez

et al. 2023

ChemMedChem

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The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3rd to 5th 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021–2022) of entirely virtual meetings, due to the COVID‐19 pandemic, the FiMC could be held in a face‐to‐face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries. The program included 38 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 102 posters were presented in two highly interactive poster sessions.

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Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)

Cited by 238 publications

References 42 publications

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Back in Person: Frontiers in Medicinal Chemistry 2023

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