An efficient synthesis of an exo-enone analogue of LL-Z1640-2 and evaluation of its protein kinase inhibitory activities

2016 ◽  
Vol 14 (2) ◽  
pp. 639-645 ◽  
Author(s):  
Stephanie Q. Wang ◽  
Shermin S. Goh ◽  
Christina L. L. Chai ◽  
Anqi Chen
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Potent Inhibitor ◽  
Reductive Coupling ◽  
Related Protein ◽  
Efficient Synthesis ◽  
Inhibitory Activities ◽  
Nanomolar Range

An exo-enone analogue of LL-Z1640-2 has been synthesised efficiently using a Ni-catalysed reductive coupling macrocyclisation of an alkyne–aldehyde. The analogue has been shown to be a potent inhibitor of several cancer related protein kinases at the nanomolar range.

Efficient synthesis of novel disubstituted pyrido[3,4-b]pyrazines for the design of protein kinase inhibitors

MedChemComm ◽  
2016 ◽  
Vol 7 (2) ◽  
pp. 224-229 ◽  
Author(s):  
Maud Antoine ◽  
Tilmann Schuster ◽  
Irene Seipelt ◽  
Babette Aicher ◽  
Michael Teifel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Related Protein ◽  
Efficient Synthesis ◽  
Aniline Derivatives

Urea and aniline derivatives were active at low micromomolar IC50 values against a panel of seven cancer-related protein kinases.

The Sucrose Non-Fermenting 1-Related Protein Kinase 2 (SnRK2) Genes Are Multifaceted Players in Plant Growth, Development and Response to Environmental Stimuli

2019 ◽  
Vol 61 (2) ◽  
pp. 225-242 ◽  
Author(s):  
Xinguo Mao ◽  
Yuying Li ◽  
Shoaib Ur Rehman ◽  
Lili Miao ◽  
Yanfei Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Specific Protein ◽  
Regulatory Mechanisms ◽  
Biological Processes ◽  
Related Protein ◽  
Biological Functions ◽  
Reversible Protein Phosphorylation ◽  
Growth Development ◽  
Regulatory Event

Abstract Reversible protein phosphorylation orchestrated by protein kinases and phosphatases is a major regulatory event in plants and animals. The SnRK2 subfamily consists of plant-specific protein kinases in the Ser/Thr protein kinase superfamily. Early observations indicated that SnRK2s are mainly involved in response to abiotic stress. Recent evidence shows that SnRK2s are multifarious players in a variety of biological processes. Here, we summarize the considerable knowledge of SnRK2s, including evolution, classification, biological functions and regulatory mechanisms at the epigenetic, post-transcriptional and post-translation levels.

scholarly journals Activation of Extracellular Signal-Related Protein Kinases 1 and 2 of the Mitogen-Activated Protein Kinase Family by Lipopolysaccharide Requires Plasma in Neutrophils from Adults and Newborns

2001 ◽  
Vol 69 (5) ◽  
pp. 3143-3149 ◽  
Author(s):  
S. Bonner ◽  
S. R. Yan ◽  
D. M. Byers ◽  
R. Bortolussi
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Oxidative Burst ◽  
Mitogen Activated Protein Kinase ◽  
Related Protein ◽  
Extracellular Signal ◽  
Oxidative Response ◽  
Mitogen Activated Protein ◽  
Mediated Priming

ABSTRACT Neutrophils exposed to low concentrations of gram-negative lipopolysaccharide (LPS) become primed and have an increased oxidative response to a second stimulus (e.g., formyl-methionyl-leucyl-phenylalanine [fMLP]). In studies aimed at understanding newborn sepsis, we have shown that neutrophils of newborns are not primed in response to LPS. To further understand the processes involved in LPS-mediated priming of neutrophils, we explored the role of extracellular signal-related protein kinases (ERK 1 and 2) of the mitogen-activated protein kinase family. We found that LPS activated ERK 1 and 2 in cells of both adults and newborns and that activation was plasma dependent (maximal at ≥5%) through LPS-binding protein. Although fibronectin in plasma is required for LPS-mediated priming of neutrophils of adults assessed by fMLP-triggered oxidative burst, it was not required for LPS-mediated activation of ERK 1 and 2. LPS-mediated activation was dose and time dependent; maximal activation occurred with approximately 5 ng of LPS per ml and at 10 to 40 min. We used the inhibitor PD 98059 to study the role of ERK 1 and 2 in the LPS-primed fMLP-triggered oxidative burst. While Western blotting showed that 100 μM PD 98059 completely inhibited LPS-mediated ERK activation, oxidative response to fMLP by a chemiluminescence assay revealed that the same concentration inhibited the LPS-primed oxidative burst by only 40%. We conclude that in neutrophils, LPS-mediated activation of ERK 1 and 2 requires plasma and that this activation is not dependent on fibronectin. In addition, we found that the ERK pathway is not responsible for the lack of LPS priming in neutrophils of newborns but may be required for 40% of the LPS-primed fMLP-triggered oxidative burst in cells of adults.

scholarly journals A pair of functionally redundant yeast genes (PPZ1 and PPZ2) encoding type 1-related protein phosphatases function within the PKC1-mediated pathway.

1993 ◽  
Vol 13 (9) ◽  
pp. 5843-5853 ◽  
Author(s):  
K S Lee ◽  
L K Hines ◽  
D E Levin
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Protein Phosphatases ◽  
Cell Lysis ◽  
Suppressor Gene ◽  
Mitogen Activated Protein Kinase ◽  
Related Protein ◽  
Mitogen Activated Protein ◽  
Yeast Genes

The PKC1 gene of Saccharomyces cerevisiae encodes a homolog of mammalian protein kinase C that is required for yeast cell growth. Loss of PKC1 function results in cell lysis due to an inability to remodel the cell wall properly during growth. The PKC1 gene has been proposed to regulate a bifurcated pathway, on one branch of which function four putative protein kinases that catalyze a linear cascade of protein phosphorylation culminating in the activation of the mitogen-activated protein kinase homolog, Mpk1p. Here we describe two genes whose overexpression suppress both an mpk1 delta mutation and a pkc1 delta mutation. One of these genes is identical to the previously identified PPZ2 gene. The PPZ2 gene is predicted to encode a type 1-related protein phosphatase and is functionally redundant with a closely related gene, designated PPZ1. Deletion of both PPZ1 and PPZ2 resulted in a temperature-dependent cell lysis defect similar to that observed for bck1 delta, mkk1,2 delta, or mpk1 delta mutants. However, ppz1,2 delta mpk1 delta triple mutants displayed a cell lysis defect at all temperatures. The additivity of the ppz1,2 delta defect with the mpk1 delta defect, combined with the results of genetic epistasis experiments, suggested either that the PPZ1- and PPZ2-encoded protein phosphatases function on a branch of the PKC1-mediated pathway different from that defined by the protein kinases or that they play an auxiliary role in the pathway. The other suppressor gene, designated BCK2 (for bypass of C kinase), is predicted to encode a 92-kDa protein that is rich in serine and threonine residues. Genetic interactions between BCK2 and other pathway components suggested that BCK2 functions on a common pathway branch with PPZ1 and PPZ2.

scholarly journals The ubiquitin-associated domain of AMPK-related protein kinases allows LKB1-induced phosphorylation and activation

2006 ◽  
Vol 394 (3) ◽  
Author(s):  
Mark H. Rider
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Related Protein ◽  
Biochemical Journal ◽  
Kinase Catalytic Domain ◽  
Uba Domain ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase)-related protein kinase subfamily of the human kinome comprises 12 members closely related to the catalytic α1/α2 subunits of AMPK. The precise role of the AMPK-related kinases and their in vivo substrates is rather unclear at present, but some are involved in regulating cell polarity, whereas others appear to control cellular differentiation. Of the 12 human AMPK-related protein kinase family members, 11 can be activated following phosphorylation of their T-loop threonine residue by the LKB1 complex. Nine of these AMPK-related kinases activated by LKB1 contain an UBA (ubiquitin-associated) domain immediately C-terminal to the kinase catalytic domain. In this issue of the Biochemical Journal, Jaleel et al. show that the presence of an UBA domain in AMP-related kinases allows LKB1-induced phosphorylation and activation. The findings have implications for understanding the molecular mechanisms of activation of this fascinating family of protein kinases. Also, mutations in the UBA domains of the AMP-related kinase genes might be present in families with Peutz–Jehgers syndrome and in other cancer patients.

A pair of functionally redundant yeast genes (PPZ1 and PPZ2) encoding type 1-related protein phosphatases function within the PKC1-mediated pathway

1993 ◽  
Vol 13 (9) ◽  
pp. 5843-5853
Author(s):  
K S Lee ◽  
L K Hines ◽  
D E Levin
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Protein Phosphatases ◽  
Cell Lysis ◽  
Suppressor Gene ◽  
Mitogen Activated Protein Kinase ◽  
Related Protein ◽  
Mitogen Activated Protein ◽  
Yeast Genes

The PKC1 gene of Saccharomyces cerevisiae encodes a homolog of mammalian protein kinase C that is required for yeast cell growth. Loss of PKC1 function results in cell lysis due to an inability to remodel the cell wall properly during growth. The PKC1 gene has been proposed to regulate a bifurcated pathway, on one branch of which function four putative protein kinases that catalyze a linear cascade of protein phosphorylation culminating in the activation of the mitogen-activated protein kinase homolog, Mpk1p. Here we describe two genes whose overexpression suppress both an mpk1 delta mutation and a pkc1 delta mutation. One of these genes is identical to the previously identified PPZ2 gene. The PPZ2 gene is predicted to encode a type 1-related protein phosphatase and is functionally redundant with a closely related gene, designated PPZ1. Deletion of both PPZ1 and PPZ2 resulted in a temperature-dependent cell lysis defect similar to that observed for bck1 delta, mkk1,2 delta, or mpk1 delta mutants. However, ppz1,2 delta mpk1 delta triple mutants displayed a cell lysis defect at all temperatures. The additivity of the ppz1,2 delta defect with the mpk1 delta defect, combined with the results of genetic epistasis experiments, suggested either that the PPZ1- and PPZ2-encoded protein phosphatases function on a branch of the PKC1-mediated pathway different from that defined by the protein kinases or that they play an auxiliary role in the pathway. The other suppressor gene, designated BCK2 (for bypass of C kinase), is predicted to encode a 92-kDa protein that is rich in serine and threonine residues. Genetic interactions between BCK2 and other pathway components suggested that BCK2 functions on a common pathway branch with PPZ1 and PPZ2.

Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants

2009 ◽  
Vol 419 (2) ◽  
pp. 247-259 ◽  
Author(s):  
Nigel G. Halford ◽  
Sandra J. Hey
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Signalling Pathways ◽  
Related Protein ◽  
Major Mechanism ◽  
Intracellular Signals ◽  
Kinase Cascade ◽  
Eukaryotic Organisms ◽  
Amp Activated Protein Kinase ◽  
Stress Signalling

The phosphorylation and dephosphorylation of proteins, catalysed by protein kinases and phosphatases, is the major mechanism for the transduction of intracellular signals in eukaryotic organisms. Signalling pathways often comprise multiple phosphorylation/dephosphorylation steps and a long-standing hypothesis to explain this phenomenon is that of the protein kinase cascade, in which a signal is amplified as it is passed from one step in a pathway to the next. This review represents a re-evaluation of this hypothesis, using the signalling network in which the SnRKs [Snf1 (sucrose non-fermenting-1)-related protein kinases] function as an example, but drawing also on the related signalling systems involving Snf1 itself in fungi and AMPK (AMP-activated protein kinase) in animals. In plants, the SnRK family comprises not only SnRK1, but also two other subfamilies, SnRK2 and SnRK3, with a total of 38 members in the model plant Arabidopsis. This may have occurred to enable linking of metabolic and stress signalling. It is concluded that signalling pathways comprise multiple levels not to allow for signal amplification, but to enable linking between pathways to form networks in which key protein kinases, phosphatases and target transcription factors represent hubs on/from which multiple pathways converge and emerge.

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