Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA)

Optimization and selectivity profiling

Carolyn D. Shomin, Scott C. Meyer, Indraneel Ghosh

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6196-6202
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number17
DOIs
StatePublished - Sep 1 2009

Fingerprint

Staurosporine
Cyclic AMP-Dependent Protein Kinases
Phosphotransferases
Ligands
Peptides
Allosteric Site
Derivatives
Peptide Library
Molecules
Bacteriophages
Substrates
Protein Kinase Inhibitors
Amides
Protein Kinases
Catalytic Domain

Keywords

  • Bivalent
  • Inhibitor
  • Kinase
  • Phage
  • Protein surface
  • Selection

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA) : Optimization and selectivity profiling. / Shomin, Carolyn D.; Meyer, Scott C.; Ghosh, Indraneel.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 17, 01.09.2009, p. 6196-6202.

Research output: Contribution to journalArticle

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