ArticleBioorganic & medicinal chemistry2009
Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): optimization and selectivity profiling.
Article in Bioorganic & medicinal chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Natural-product-based fluorescent probes: recent advances and applications.RSC medicinal chemistry · 2023Review
- Cell-impermeable staurosporine analog targets extracellular kinases to inhibit HSV and SARS-CoV-2.Communications biology · 2022Article
- Targeting kinase signaling pathways with constrained peptide scaffolds.Pharmacology & therapeutics · 2017Review
- An efficient strategy to enhance binding affinity and specificity of a known isozyme inhibitor.Organic & biomolecular chemistry · 2016Article
- Alkylation of Staurosporine to Derive a Kinase Probe for Fluorescence Applications.ChemMedChem · 2016Article
- Conversion of a Single Polypharmacological Agent into Selective Bivalent Inhibitors of Intracellular Kinase Activity.ACS chemical biology · 2016Article
- Targeting diverse signaling interaction sites allows the rapid generation of bivalent kinase inhibitors.ACS chemical biology · 2012Article
- Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.Journal of medicinal chemistry · 2012Article
- Iterative in situ click chemistry assembles a branched capture agent and allosteric inhibitor for Akt1.Journal of the American Chemical Society · 2011Article
- Selection of cyclic-peptide inhibitors targeting Aurora kinase A: problems and solutions.Bioorganic & medicinal chemistry · 2011Article
- Bivalent inhibitors of the tyrosine kinases ABL and SRC: determinants of potency and selectivity.Molecular bioSystems · 2011Article
- A coiled-coil enabled split-luciferase three-hybrid system: applied toward profiling inhibitors of protein kinases.Journal of the American Chemical Society · 2010Article
- Bivalent inhibitors of protein kinases.Critical reviews in biochemistry and molecular biologyReview
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
We have recently developed a fragment based selection strategy for targeting kinases, where a small molecule warhead can be non-covalently tethered to a phage-displayed library of peptides. This approach was applied to the conversion of the promiscuous kinase inhibitor, staurosporine, into a potent bivalent ligand for cAMP-dependent protein kinase (PKA). Herein we report a systematic evaluation of this new bivalent ligand (BL); (a) Lineweaver-Burke analysis revealed that the BL, unlike substrate-based bivalent kinase inhibitors, displayed non-competitive inhibition with respect to the peptide substrate, suggesting an allosteric mechanism of action; (b) linker optimization of the BL, afforded one of the most potent, sub-nanomolar, inhibitors of PKA reported to date; (c) the BL was found to be modular, where attachment of active site targeted small molecule warheads in lieu of staurosporine could achieve similar gains in affinity; and (d) profiling studies of both the staurosporine derivative and the BL (amide isostere) against a panel of 90 kinases revealed almost unique enhancement in selectivity against PKA (>5-fold) compared to the starting staurosporine derivative. These combined results provide new insights for BL discovery, which has the potential to provide guidance toward the development of kinase selective reagents while uncovering new allosteric sites on kinases for therapeutic targeting.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.