Conformation-tunable ATP-competitive kinase inhibitors
Michael P Agius1, Kristin Ko1, Taylor K Johnson1
1Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109, USA. soellner@umich.edu.
Chemical Communications (Cambridge, England)
|February 23, 2022
Summary
New kinase inhibitors were designed to target protein conformation, not just enzymatic activity. This research provides tools to explore how protein shape influences kinase signaling and drug efficacy.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Small molecule kinase inhibitors are clinically valuable, with over 60 approved drugs.
- The precise mechanisms underlying kinase inhibitor efficacy, including non-catalytic functions, are not fully understood.
Purpose of the Study:
- To design and synthesize conformation-selective kinase inhibitors.
- To investigate the role of protein conformation in kinase signaling and inhibitor efficacy.
- To develop a toolset for studying conformation-tunable kinase inhibitors.
Main Methods:
- Designed and synthesized pyrazolopyrimidine-based kinase inhibitors targeting c-Src kinase conformation.
- Developed three pairs of conformation-selective kinase inhibitors with distinct hinge-binding scaffolds.
- Screened inhibitors against 468 kinases and evaluated binding to mutant kinases (EGFR, FLT3, KIT).
Main Results:
- Identified 38 kinases amenable to study using the developed inhibitor pairs.
- Demonstrated the ability of inhibitors to modulate global kinase conformation.
- Explored inhibitor binding to mutant forms of key kinases like EGFR, FLT3, and KIT.
Conclusions:
- Conformation-selective kinase inhibitors offer new therapeutic strategies.
- Protein conformation plays a critical role in kinase signaling.
- The developed compounds provide valuable tools for further research into kinase inhibitor mechanisms.
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