Structure
Division of Biological Chemistry and Molecular Microbiology, University of Dundee, Dundee DD1 5EH, Scotland.
Published: February 2004
LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.
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http://dx.doi.org/10.1016/j.str.2004.01.005 | DOI Listing |
Pharmaceuticals (Basel)
August 2023
School of Chemistry and ABCRF, University College Cork, Western Road, T12K8AF Cork, Ireland.
The evolution of bisindolyl maleimides and indolyl maleimide derivatives and their unique biological activities have stimulated great interest in medicinal chemistry programs. Bisindolylmaleimide (BIM)-type compounds arise from natural sources such as arcyriarubin and are biosynthetically related to indolocarbazoles. BIMs are commonly the immediate synthetic precursors of indolocarbazoles, lacking a central bond between the two aromatic units and making them more flexible and drug-like.
View Article and Find Full Text PDFDev Neurobiol
June 2014
Department of Biological Science and Neuroscience Research Center, University at Albany, State University of New York, Albany, New York, 12222.
The developing zebrafish retinotectal arbors make many trial branches with synapses but most are retracted. With NMDA blockers, branches are withdrawn at a higher rate, and a synapse on a branch not only stabilizes that branch, but biases new branches to form nearby. Here, we tested whether new branch formation requires the polarity complex, which is essential for organizing the cytoskeleton in initial axon formation.
View Article and Find Full Text PDFEur J Pharmacol
June 2011
Department of Veterinary Pharmacology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Prostaglandin E2 (PGE2) is one major prostanoid produced under inflammatory situation. Although PGE2 is known to induce vascular contraction, its detailed mechanism remains unknown. In the present study, we investigated the signaling pathway underlying PGE2-induced smooth muscle contraction in rat mesenteric artery.
View Article and Find Full Text PDFNucl Med Biol
October 2010
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Bisindolylmaleimide MKC-1 (formerly known as Ro 31-7453) is a novel, orally active, small-molecule, cell cycle inhibitor with broad-spectrum antitumor effects. [(11)C]MKC-1 ([(11)C]Ro 31-7453) was first designed and synthesized as a new potential positron emission tomography cancer imaging agent through two different strategies. The first strategy was to prepare a carbon-11-labeled bisindolyl maleic anhydride intermediate followed by the conversion to maleimide.
View Article and Find Full Text PDFJ Hypertens
September 2010
Division of Cardiovascular Sciences, Centre for Applied Medical Research, Pamplona, Spain.
Objectives: Hyperleptinemia and oxidative stress play a major role in the development of cardiovascular diseases in obesity. This study aimed to investigate whether there is a relationship between plasma levels of leptin and phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and its potential relevance in the vascular remodeling in obese patients.
Methods: The study was performed in 164 obese and 94 normal-weight individuals (controls).
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