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.
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.
Current Medicinal Chemistry
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,United States
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.
Export Options
About this article
Cite this article as:
Verkhivker M. Gennady*, Leveraging Structural Diversity and Allosteric Regulatory Mechanisms of Protein Kinases in the Discovery of Small Molecule Inhibitors, Current Medicinal Chemistry 2017; 24 (42) . https://dx.doi.org/10.2174/0929867323666161006113418
DOI https://dx.doi.org/10.2174/0929867323666161006113418 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the Treatment of Chronic Inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Hormetic Potential of Sulforaphane (SFN) in Switching Cells’ Fate Towards Survival or Death
Mini-Reviews in Medicinal Chemistry Plant Secondary Metabolites in Cancer Chemotherapy: Where are We?
Current Pharmaceutical Biotechnology Oxadiazole Derivatives as Anticancer and Immunomodulatory Agents: A Systematic Review
Current Medicinal Chemistry Anti-Cancer Therapies that Utilize Cell Penetrating Peptides
Recent Patents on Anti-Cancer Drug Discovery Magnetic Nanoparticles: New Players in Antimicrobial Peptide Therapeutics.
Current Protein & Peptide Science A Retrospective Study on <i>Gloriosa superba</i> and Its Main Active Constituents
The Natural Products Journal Intracellular Redox State as Target for Anti-Influenza Therapy: Are Antioxidants Always Effective?
Current Topics in Medicinal Chemistry The Sodium-Iodide Symporter
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Star Shaped Poly(ethylene glycols) Yield Biocompatible Gene Delivery Systems
Pharmaceutical Nanotechnology Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction
CNS & Neurological Disorders - Drug Targets The Klf6 Super-enhancer Determines Klf6 Sensitivity to BRD4 Inhibitors in Human Hepatoma (HepG2) Cells
Current Biotechnology Reality Check: Cancer Stem Cell Route to Cancer
Current Biotechnology Identification and Characterization of SNP Mutation in Genes Related to Non-small Cell Lung Cancer
Current Signal Transduction Therapy The Use of Therapeutic Peptides to Target and to Kill Cancer Cells
Current Medicinal Chemistry Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Biologically Active Agents
Current Medicinal Chemistry Design, Synthesis, and Biological Evaluation of Some Novel Retinoid Derivatives
Letters in Drug Design & Discovery Potential of Photobiomodulation to Induce Differentiation of Adipose- Derived Mesenchymal Stem Cells into Neural Cells
Current Stem Cell Research & Therapy Clonetics
Current Drug Metabolism Interferon Therapy in Lung Cancer: Current Perspectives
Current Cancer Therapy Reviews Intraorganellar Acidification by V-ATPases: A Target in Cell Proliferation and Cancer Therapy
Recent Patents on Anti-Cancer Drug Discovery