[PDF] Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). | Semantic Scholar (2024)

The small molecule GSK2334470 is described, which inhibits PDK1 with an IC50 of ∼10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related toPDK1 at 500fold higher concentrations, and will be a useful tool for delineating the roles of PDK 1 in biological processes.

The small molecule GSK2334470 is described, which inhibits PDK1 with an IC₅₀ of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK2 at 500-fold higher concentrations, and is suggested to be a useful tool for delineating the roles ofPDK1 in biological processes.

PF-4708671 is reported, a potent and highly selective inhibitor of S6K1 (p70 S6 kinase 1) in vitro and in cells, which is the first reported inhibitor that is highly selective for S 6K1.

The title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signaling and shows a high selectivity over kinases with an equivalently positioned cysteine, as well as in a larger kinase panel.

It is reported that H89 (N-(2-(4-bromocinnamylamino) ethyl)-5-isoquinolinesulfonamide), a well-characterized ATP-mimetic kinase inhibitor, renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors across multiple cell lines.

It is demonstrated that the p70S6K specific inhibitor PF-4708671 has inhibitory effects on NSCLC tumorigenesis in vitro and in vivo, and P70S 6K should be considered a new potential therapeutic target, and PF- 470867 may be used as targeted drug for cancer treatment.

The results suggest further work is warranted to explore the utility of combining PDK1 and mTOR inhibitors as a therapeutic strategy for treatment of cancers that harbour mutations elevating Akt activity.

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The small molecule BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells.

The findings demonstrate the existence of a family of rapamycin-sensitive protein kinases potentially involved in S6 phosphorylation, translational control, and transduction of mTOR signals.

The small molecule Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

It is shown that S6 kinase 1 (S6K1), but not Akt, directly phosphorylates mTOR in cell-free in vitro system and in cells, and phosphorylated at threonine 2446/serine 2448, which has been shown previously to be part of a regulatory repressor domain.

It is demonstrated here that Rictor is a direct target of the ribosomal protein S6 kinase-1 (S6K1), which reveals an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.

PDK1 is required for activation of members of the AGC kinase family; it is shown that two such kinases, p70 S6 kinase (regulated via mTOR) and p90RSK1 (activated by Erk) phosphorylate eEF2k at a conserved serine and inhibit its activity.

The structures offer insights into the structural basis of the 3′-phosphoinositide-dependent kinase-1-induced activation of p70S6K and provide a platform for the rational structure-guided design of specific p70s6K inhibitors.

Harmine has been identified as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro and the results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes.

It is demonstrated that homozygous disruption of the p70s 6k/p85s6k gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis, and the finding of a new S6 kinase gene, which can partly compensate for p70S6k/ p85s 6K function, underscores the importance of S6K function in cell growth.

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