scholarly journals Enzyme kinetics and distinct modulation of the protein kinase N family of kinases by lipid activators and small molecule inhibitors

2014 ◽  
Vol 34 (2) ◽  
Author(s):  
Matthew D. Falk ◽  
Wei Liu ◽  
Ben Bolaños ◽  
Keziban Unsal-Kacmaz ◽  
Anke Klippel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinetic Analysis ◽  
Enzyme Kinetics ◽  
Small Molecule ◽  
Targeted Therapies ◽  
Small Molecule Inhibitors ◽  
Kinetic Mechanism ◽  
Protein Kinase N ◽  
Isoform Selectivity

We conducted kinetic analysis of the relatively unexplored PKN family and effects of lipids, and identified potent inhibitors with various isoform selectivity. The kinetic mechanism, lipid activators and inhibitors could be useful for understanding PKN biology and developing PKN-targeted therapies.

scholarly journals Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice

2018 ◽  
Vol 84 (3) ◽  
pp. 193-201 ◽  
Author(s):  
Angelo Blasio ◽  
Jingyi Wang ◽  
Dan Wang ◽  
Florence P. Varodayan ◽  
Matthew B. Pomrenze ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Ethanol Consumption ◽  
Kinase C ◽  
Protein Kinase C Epsilon

scholarly journals A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency

2020 ◽  
Vol 117 (40) ◽  
pp. 24802-24812 ◽  
Author(s):  
Salima Daou ◽  
Manisha Talukdar ◽  
Jinle Tang ◽  
Beihua Dong ◽  
Shuvojit Banerjee ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Protein Kinase Inhibitors ◽  
Response To Treatment ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
In Cells

The oligoadenylate synthetase (OAS)–RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential.

SMART Drug Design: Novel Phosphopeptide and ATP Mimetic-Based Small Molecule Inhibitors of the Oncogenic Protein Kinase pp60src (Src)

2005 ◽  
pp. 219-253 ◽  
Author(s):  
T. K. Sawyer ◽  
R. S. Bohacek ◽  
W. C. Shakespeare ◽  
C. A. Metcalf ◽  
Y. Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Drug Design ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Oncogenic Protein ◽  
Smart Drug

scholarly journals Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondii

2013 ◽  
Vol 56 (7) ◽  
pp. 3068-3077 ◽  
Author(s):  
Sebastian Lourido ◽  
Chao Zhang ◽  
Michael S. Lopez ◽  
Keliang Tang ◽  
Jennifer Barks ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinase

scholarly journals Novel Small Molecule Inhibitors of Protein Kinase D Suppress NF-kappaB Activation and Attenuate the Severity of Rat Cerulein Pancreatitis

2017 ◽  
Vol 8 ◽  
Author(s):  
Jingzhen Yuan ◽  
Tanya Tan ◽  
Meng Geng ◽  
Grace Tan ◽  
Chintan Chheda ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Protein Kinase D ◽  
Nf Kappab

scholarly journals In vitro and In vivo Activity of Novel Small-Molecule Inhibitors Targeting the Pleckstrin Homology Domain of Protein Kinase B/AKT

2009 ◽  
Vol 69 (12) ◽  
pp. 5073-5081 ◽  
Author(s):  
Sylvestor A. Moses ◽  
M. Ahad Ali ◽  
Song Zuohe ◽  
Lei Du-Cuny ◽  
Li Li Zhou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Protein Kinase B ◽  
Pleckstrin Homology Domain ◽  
Pleckstrin Homology

scholarly journals Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains

2021 ◽  
Author(s):  
Karen T Elvers ◽  
Magdalena Lipka-Lloyd ◽  
Rebecca C Trueman ◽  
Benjamin David Bax ◽  
Youcef Mehellou
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Protein Kinase ◽  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Domain Specific ◽  
Wnk Kinases ◽  
And Oxidative Stress

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and Oxidative Stress Responsive 1 (OSR1) kinase are two serine/threonine protein kinase that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream With No Lysine Kinases (WNKs), facilitating their activation via phosphorylation. Thus, the inhibition of SPAK and OSR1 binding, via their CCT domains, to WNK kinases is a plausible strategy for inhibiting SPAK and OSR1 kinases. To facilitate structure-guided drug design of such inhibitors, we expressed and purified human SPAK and OSR1 CCT domains and solved their crystal structures. We also employed a biophysical strategy and determined the affinity of SPAK and OSR1 CCT domains to an 18-mer peptide derived from WNK4. Together, the crystal structures and affinity data reported herein provide a robust platform to facilitate the design of CCT domain specific small molecule inhibitors of SPAK-activation by WNK kinases, potentially leading to new improved treatments for hypertension and ischemic stroke.

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