Leveraging Structural Diversity and Allosteric Regulatory Mechanisms of Protein Kinases in the Discovery of Small Molecule Inhibitors

• Published in: Current medicinal chemistry Vol. 24; no. 42; p. 4838
• Main Author: Verkhivker, Gennady M
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2017
• Subjects: Allosteric Regulation - drug effects; Drug Discovery; Humans; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; computational modeling of protein kinases; BRAF paradoxical activation; multiscale simulations; kinase residue interaction networks; BRAF kinases; allosteric kinase inhibitors; dimerization-induced kinase activation; ErbB kinases; allosteric regulation
• DOI: 10.2174/0929867323666161006113418

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.