Strategies for the Selective Regulation of Kinases with Allosteric Modulators: Exploiting Exclusive Structural Features
Abstract
The modulation of kinase function has become an important goal in modern drug discovery and chemical biology research. In cancer-targeted therapies, kinase inhibitors have been experiencing an upsurge, which can be measured by the increasing number of kinase inhibitors approved by the FDA in recent years. However, lack of efficacy, limited selectivity, and the emergence of acquired drug resistance still represent major bottlenecks in the clinic and challenge inhibitor development. Most known kinase inhibitors target the active kinase and are ATP competitive. A second class of small organic molecules, which address remote sites of the kinase and stabilize enzymatically inactive conformations, is rapidly moving to the forefront of kinase inhibitor research. Such allosteric modulators bind to sites that are less conserved across the kinome and only accessible upon conformational changes. These molecules are therefore thought to provide various advantages such as higher selectivity and extended drug target residence times. This review highlights various strategies that have been developed to utilizing exclusive structural features of kinases and thereby modulating their activity allosterically.
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Similar considerations delayed development of protein kinase inhibitors, and some of the best kinase inhibitors are allosteric inhibitors that lock the conformation of kinases such as MEK in a closed state.
“Similar considerations delayed development of protein kinase inhibitors, and indeed some of the best kinase inhibitors proved to not be competitive with ATP, but are allosteric inhibitors that lock the conformation of kinases such as MEK in a closed state23.”
From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [23]
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- Authors
- Fang, Z., Grütter, C., & Rauh, D.
- Affiliations
- TU Dortmund University (DE)
- Corresponding author
- Rauh, Daniel
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-12-31
- Volume
- 8
- Issue
- 1
- Pages
- 58-70
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2050972073
- Cited by
- 197
- References
- 6
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 17 · 2019: 18 · 2018: 13 · 2017: 15 · 2016: 16 · 2015: 23 · 2014: 27 · 2013: 10
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- kinase inhibitors, kinase selectivity, ATP-competitive inhibitors, drug resistance, cancer drug targets
- MeSH terms
- Allosteric Regulation, Binding, Competitive, Humans, Molecular Conformation, Protein Kinases, Drug Delivery Systems, Protein Kinase Inhibitors
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