1-NA-PP1 - CAS 221243-82-9
Catalog number: 221243-82-9
Category: Inhibitor
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1-NA-PP1 is a reversible, cell-permeable inhibitor of Src-family tyrosine kinases that have been mutated, by a single base substitution, to become 'analog sensitive' (as), as compared to the wild-type kinase.
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1.New pyrazolopyrimidine inhibitors of protein kinase d as potent anticancer agents for prostate cancer cells.
Tandon M1, Johnson J, Li Z, Xu S, Wipf P, Wang QJ. PLoS One. 2013 Sep 23;8(9):e75601. doi: 10.1371/journal.pone.0075601. eCollection 2013.
The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search for potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe the identification, in vitro characterization, structure-activity analysis, and biological evaluation of a novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 and IKK-16 were identified as pan-PKD inhibitors in a small-scale targeted kinase inhibitor library assay. Both screening hits inhibited PKD isoforms at about 100 nM and were ATP-competitive inhibitors. Analysis of several related kinases indicated that 1-NA-PP1 was highly selective for PKD as compared to IKK-16. SAR analysis showed that 1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest.
2.A chemical-genetic approach to elucidate protein kinase function in planta.
Böhmer M1, Romeis T. Plant Mol Biol. 2007 Dec;65(6):817-27. Epub 2007 Oct 9.
The major objective in protein kinase research is the identification of the biological process, in which an individual enzyme is integrated. Protein kinase-mediated signalling is thereby often addressed by single knock-out mutation- or co-suppression-based reverse genetics approaches. If a protein kinase of interest is a member of a multi gene family, however, no obvious phenotypic alteration in the morphology or in biochemical parameters may become evident because mutant phenotypes may be compensated by functional redundancy or homeostasis. Here we establish a chemical-genetic screen combining ATP-analogue sensitive (as) kinase variants and molecular fingerprinting techniques to study members of the plant calcium-dependent protein kinase (CDPK) family in vivo. CDPKs have been implicated in fast signalling responses upon external abiotic and biotic stress stimuli. CDPKs carrying the as-mutation did not show altered phosphorylation kinetics with ATP as substrate, but were able to use ATP analogues as phosphate donors or as kinase inhibitors.
3.Aurora A is involved in central spindle assembly through phosphorylation of Ser 19 in P150Glued.
Reboutier D1, Troadec MB, Cremet JY, Chauvin L, Guen V, Salaun P, Prigent C. J Cell Biol. 2013 Apr 1;201(1):65-79. doi: 10.1083/jcb.201210060.
Knowledge of Aurora A kinase functions is limited to premetaphase events, particularly centrosome maturation, G2/M transition, and mitotic spindle assembly. The involvement of Aurora A in events after metaphase has only been suggested because appropriate experiments are technically difficult. We report here the design of the first human Aurora A kinase (as-AurA) engineered by chemical genetics techniques. This kinase is fully functional biochemically and in cells, and is rapidly and specifically inhibited by the ATP analogue 1-Naphthyl-PP1 (1-Na-PP1). By treating cells exclusively expressing the as-AurA with 1-Na-PP1, we discovered that Aurora A is required for central spindle assembly in anaphase through phosphorylation of Ser 19 of P150Glued. This paper thus describes a new Aurora A function that takes place after the metaphase-to-anaphase transition and a new powerful tool to search for and study new Aurora A functions.
4.Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice.
Maiya R1, McMahon T2, Wang D2, Kanter B2, Gandhi D1, Chapman HL1, Miller J2, Messing RO3. Neuropharmacology. 2016 Mar 3;107:40-48. doi: 10.1016/j.neuropharm.2016.02.036. [Epub ahead of print]
Reducing expression or inhibiting translocation of protein kinase C epsilon (PKCε) prolongs ethanol intoxication and decreases ethanol consumption in mice. However, we do not know if this phenotype is due to reduced PKCε kinase activity or to impairment of kinase-independent functions. In this study, we used a chemical-genetic strategy to determine whether a potent and highly selective inhibitor of PKCε catalytic activity reduces ethanol consumption. We generated ATP analog-specific PKCε (AS-PKCε) knock-in mice harboring a point mutation in the ATP binding site of PKCε that renders the mutant kinase highly sensitive to inhibition by 1-tert-butyl-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine (1-NA-PP1). Systemically administered 1-NA-PP1 readily crossed the blood brain barrier and inhibited PKCε-mediated phosphorylation. 1-NA-PP1 reversibly reduced ethanol consumption by AS-PKCε mice but not by wild type mice lacking the AS-PKCε mutation.
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CAS 221243-82-9 1-NA-PP1

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