Use of Protein Kinase-Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors

SLAS Discovery
Ana C Puhl-RubioKenneth H Pearce

Abstract

Inositol hexakisphosphate kinases (IP6Ks) regulate a myriad of cellular processes, not only through their catalytic activity (which synthesizes InsP7, a multifunctional inositol pyrophosphate signaling molecule) but also through protein-protein interactions. To further study the enzymatic function and distinguish between these different mechanisms, specific inhibitors that target IP6K catalytic activity are required. Only one IP6K inhibitor is commonly used: N2-( m-(trifluoromethyl)benzyl) N6-( p-nitrobenzyl)purine (TNP). TNP is, however, compromised by weak potency, inability to distinguish between IP6K isoenzymes, off-target activities, and poor pharmacokinetic properties. Herein, we describe a new inhibitor discovery strategy, based on the high degree of structural conservation of the nucleotide-binding sites of IP6Ks and protein kinases; we screened for novel IP6K2 inhibitors using a focused set of compounds with features known, or computationally predicted, to target nucleotide binding by protein kinases. We developed a time-resolved fluorescence resonance energy transfer (TR-FRET) assay of adenosine diphosphate (ADP) formation from adenosine triphosphate (ATP). Novel hit compounds for IP6K2 were identified and validated w...Continue Reading

References

Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·S M VoglmaierS H Snyder
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Rashna BhandariSolomon H Snyder
Nov 29, 2011·Nature Chemical Biology·Huanchen WangStephen B Shears
May 2, 2014·Nucleic Acids Research·Marco BiasiniTorsten Schwede
Jan 27, 2015·Proceedings of the National Academy of Sciences of the United States of America·Feng RaoSolomon H Snyder
Sep 4, 2015·Journal of Biosciences·Swarna Gowri Thota, Rashna Bhandari
Sep 12, 2015·Bioorganic & Medicinal Chemistry·Li XingElizabeth A Lunney
Oct 27, 2015·Nature Biotechnology·Jonathan M ElkinsWilliam J Zuercher
Nov 2, 2016·The Journal of Clinical Investigation·Qingzhang ZhuAnutosh Chakraborty
Sep 20, 2017·Nature Chemical Biology·Kimberly D BarnashStephen V Frye

❮ Previous
Next ❯

Citations

Mar 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sandip MukherjeeAnutosh Chakraborty

❮ Previous
Next ❯

Methods Mentioned

BETA
electrophoresis
Assay
fluorescence resonance
X-ray
Kinase Assay

Software Mentioned

GraphPad Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.