Covalent-Allosteric Kinase Inhibitors

Angew Chem Int Ed Engl. 2015 Aug 24;54(35):10313-6. doi: 10.1002/anie.201502142. Epub 2015 Jun 25.


Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research.

Keywords: cancer; drug design; inter-domain interactions; medicinal chemistry; tumor thermapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Allosteric Regulation
  • Binding, Competitive
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Signal Transduction / drug effects*


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt