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Published on: September 15, 2017
Small-molecule protein and lipid kinase inhibitors in inflammation and specific models for their evaluation
Matthias Gaestel1, Alexey Kotlyarov
1Hannover Medical School, Institute of Biochemistry, Hannover, Germany. gaesPhonematthias@mh-hannover.de
Abstract:
The inflammatory response requires complex and coordinated cooperation of different signaling pathways and cell types. Therefore, more than 40 different protein or lipid kinases can be regarded as potential small-molecule inhibitor targets to approach a therapy of acute inflammation, such as septic syndrome, and especially chronic inflammation, such as rheumatoid arthritis or inflammatory bowel disease. Besides the general considerations about selectivity and potency of small-molecule kinase inhibitors, in this chapter special emphasis is put on the inflammation-specific methods and assays available for testing potential small-molecule inhibitors for their anti-inflammatory activity. Examples for human cell-based assays for characterization of the effect of inhibitors on contribution of various cell types, such as monocytes, neutrophils, mast cells, T-cells, and synovial fibroblasts, to the inflammatory scenario are given. It is further demonstrated how these assays are complemented by rodent models for septic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and systemic lupus erythematosus. Finally, it is discussed how the results obtained by these methods can be further validated and which future strategies for the treatment of chronic inflammation will exist.
Insights
Targeting protein and lipid kinases with small-molecule inhibitors offers a promising therapeutic strategy for acute and chronic inflammatory diseases. This review highlights inflammation-specific assays and models for evaluating anti-inflammatory drug candidates.
Area of Science:
- Pharmacology and Drug Discovery
- Immunology and Inflammation Research
- Medicinal Chemistry
Background:
- Inflammation involves complex signaling pathways and diverse cell types, necessitating multifaceted therapeutic approaches.
- Protein and lipid kinases are key regulators of inflammatory signaling, representing over 40 potential targets for small-molecule inhibitors.
- Effective treatments for acute (e.g., septic syndrome) and chronic inflammatory conditions (e.g., rheumatoid arthritis, inflammatory bowel disease) are in high demand.
Purpose of the Study:
- To review inflammation-specific methods and assays for evaluating the anti-inflammatory activity of small-molecule kinase inhibitors.
- To provide examples of human cell-based assays and rodent models for characterizing inhibitor efficacy.
- To discuss future strategies for the development of novel anti-inflammatory therapies.
Main Methods:
- Utilized human cell-based assays to assess inhibitor effects on key inflammatory cells (monocytes, neutrophils, mast cells, T-cells, synovial fibroblasts).
- Employed rodent models for various inflammatory conditions, including septic syndrome, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and systemic lupus erythematosus.
- Focused on selectivity and potency considerations for small-molecule kinase inhibitors in the context of inflammation.
Main Results:
- Demonstrated the utility of specific cell-based assays in characterizing the impact of kinase inhibitors on distinct cellular contributions to inflammation.
- Showcased the complementary role of established animal models in validating the in vitro findings and assessing therapeutic potential.
- Provided a framework for validating experimental results and exploring future therapeutic avenues.
Conclusions:
- Small-molecule kinase inhibitors represent a viable therapeutic strategy for managing inflammatory diseases.
- A combination of human cell-based assays and relevant animal models is crucial for effective drug development and validation.
- Further research into kinase-targeted therapies holds significant promise for treating chronic inflammatory conditions.
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Major types that are helpful drug targets include: