Identification of novel classes of protein kinase inhibitors using combinatorial peptide chemistry based on functional genomics knowledge

Thomas J. Lukas, Salida Mirzoeva, Urszula Slomczynska, D. Martin Watterson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

A discovery approach based on an intramolecular inhibitory mechanism was applied to a prototype calmodulin (CaM)-regulated protein kinase in order to demonstrate a proof-of-principle for the development of selective inhibitors. The overall approach used functional genomics analysis of myosin light chain kinase (MLCK) to identify short autoinhibitory sequences that lack CaM recognition activity, followed by recursive combinatorial peptide library production and comparative activity screens. Peptide 18 (Arg-Lys-Lys-Tyr- Lys-Tyr-Arg-Arg-Lys-NH2), one of several selective inhibitors discovered, has an IC50 = 50 nM for MLCK, inhibits CaM kinase II only at 4000-fold higher concentrations, and does not inhibit cyclic AMP-dependent protein kinase. Analogues of peptide 18 containing conformationally constrained cis- 4-aminocyclohexanecarboxylic acid retained affinity and selectivity. The inhibitors add to the armamentarium available for the deconvolution of complex signal transduction pathways and their relationship to homeostasis and disease, and the approach is potentially applicable to enzymes in which the catalytic and regulatory domains are found within the same open reading frame of a cDNA.

Original languageEnglish (US)
Pages (from-to)910-919
Number of pages10
JournalJournal of Medicinal Chemistry
Volume42
Issue number5
DOIs
StatePublished - Mar 11 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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