Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A

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

Research output: Contribution to journalArticle

Abstract

We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.

Original languageEnglish (US)
Pages (from-to)13812-13813
Number of pages2
JournalJournal of the American Chemical Society
Volume129
Issue number45
DOIs
StatePublished - Nov 14 2007
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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