Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases

J Med Chem. 2009 Jan 22;52(2):308-21. doi: 10.1021/jm800797n.

Abstract

The crystal structure of a complex of the catalytic subunit (type alpha) of cAMP-dependent protein kinase (PKA C alpha) with ARC-type inhibitor (ARC-1034), the presumed lead scaffold of previously reported adenosine-oligo-arginine conjugate-based (ARC-type) inhibitors, was solved. Structural elements important for interaction with the kinase were established with specifically modified derivatives of the lead compound. On the basis of this knowledge, a new generation of inhibitors, conjugates of adenosine-4'-dehydroxymethyl-4'-carboxylic acid moiety and oligo(D-arginine), was developed with inhibitory constants well into the subnanomolar range. The structural determinants of selectivity of the new compounds were established in assays with ROCK-II and PKBgamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Amino Acid Sequence
  • Animals
  • Basophils / enzymology*
  • Catalytic Domain
  • Cattle
  • Crystallography
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Fluorescence Polarization
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Sequence Homology, Amino Acid

Substances

  • ARC 1034
  • Dipeptides
  • Protein Kinase Inhibitors
  • Cyclic AMP-Dependent Protein Kinases
  • Adenosine