Title:Leveraging Structural Diversity and Allosteric Regulatory Mechanisms of Protein Kinases in the Discovery of Small Molecule Inhibitors
VOLUME: 24 ISSUE: 42
Author(s):Gennady M. Verkhivker*
Affiliation:Department of Computational Sciences, Faculty of Physics, Computational Science and Engineering, Schmid College of Science & Technology, Chapman University, Orange, CA 92866
Keywords:ErbB kinases, BRAF kinases, dimerization-induced kinase activation, BRAF paradoxical activation,
allosteric regulation, allosteric kinase inhibitors, computational modeling of protein kinases, multiscale simulations,
kinase residue interaction networks.
Abstract:Protein kinases are versatile molecule switches that govern functional processes in
signal transduction networks and regulate fundamental biological processes of cell cycle and
organism development. The continuous growth of biological information and a remarkable
breath of structural, genetic, and pharmacological studies on protein kinase genes have significantly
advanced our knowledge of the kinase activation, drug binding and allosteric mechanisms
underlying kinase regulation and interactions in signaling cascades.. Structural and biochemical
studies of the genetic and molecular determinants of protein kinases binding with
inhibitors have been the cornerstone of drug discovery efforts in clinical oncology leading to
proliferation of effective anticancer therapies. Recent advances in understanding allosteric
regulation of protein kinases have fueled unprecedented efforts aiming in the discovery of targeted
and allosteric kinase inhibitors that can combat cancer mutants and are at the forefront of
the precision medicine initiative in oncology. Despite diversity of regulatory scenarios underlying
kinase functions, dimerization-driven activation is a common mechanism of allosteric
regulation that is shared by many protein kinase families, most notably ErbB and BRAF
kinases that play a central role in growth factor signaling and human disease. In this review,
we focused on structural, biochemical and computational studies of the ErbB and BRAF
kinases and discuss how diversity of the structural landscape for these kinase genes and dimerization-
dependent mechanisms of their regulation can be leveraged in the design and discovery
of kinase inhibitors and allosteric modulators of kinase activation. The lessons from
this analysis could inform discovery of specific targeted therapies and robust drug combinations
for cancer treatment.
