10.1021/jm980573a.s001
Thomas J. Lukas
Thomas
J. Lukas
Salida Mirzoeva
Salida
Mirzoeva
Urszula Slomczynska
Urszula
Slomczynska
D. Martin Watterson
D. Martin
Watterson
Identification of Novel Classes of Protein Kinase Inhibitors Using
Combinatorial Peptide Chemistry Based on Functional Genomics Knowledge
American Chemical Society
1999
Novel Classes
CaM kinase II
myosin light chain kinase
reading frame
50 nM
activity screens
genomics analysis
discovery approach
autoinhibitory sequences
Protein Kinase Inhibitors
prototype calmodulin
combinatorial peptide library production
Combinatorial Peptide Chemistry
MLCK
Peptide 18
IC 50
protein
peptide 18
lack CaM recognition activity
signal transduction pathways
Functional Genomics Knowledge
1999-02-24 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Identification_of_Novel_Classes_of_Protein_Kinase_Inhibitors_Using_Combinatorial_Peptide_Chemistry_Based_on_Functional_Genomics_Knowledge/3684066
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<b> 18</b> (Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH<sub>2</sub>), one
of several selective inhibitors discovered, has an IC<sub>50</sub> = 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<b> 18 </b>containing conformationally constrained <i>cis</i>-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.