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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Update on lymphocyte specific kinase inhibitors: a patent survey
Matthew W Martin1, Michelle R Machacek
1Amgen, Inc., Department of Medicinal Chemistry, Cambridge, Massachusetts 02142, USA. matthew.martin@amgen.com
Importance Of The Field:
Lck (p56(lck) or lymphocyte specific kinase) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T cell receptor (TCR)-mediated signaling, leading to normal T-cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection.
Areas Covered In This Review:
This review covers the patents, patent applications and associated publications for small molecule kinase inhibitors of Lck since 2005 and attempts to place them in context from a structural point of view.
What The Reader Will Gain:
Readers will gain an overview of the structural classes and binding modes of Lck inhibitors, the major players in this area and an insight into the current state of the field.
Take Home Message:
The search for a potent and orally active inhibitor of Lck has been an intense area of research for a number of years. Despite tremendous efforts, the identification of a highly selective and potent Lck inhibitor suitable for use as an immunosuppressive agent remains elusive.
Insights
Despite extensive research, a potent and selective Lck inhibitor for treating T-cell-mediated diseases remains elusive. This review details small molecule inhibitors targeting lymphocyte-specific kinase (Lck) since 2005.
Area of Science:
- Biochemistry
- Immunology
- Drug Discovery
Background:
- Lymphocyte-specific kinase (Lck) is crucial for T-cell receptor signaling and T-cell development.
- Genetic studies confirm Lck's critical role in T-cell activation.
- Targeting Lck offers potential therapeutic strategies for autoimmune diseases and transplant rejection.
Purpose of the Study:
- To review patents and publications of small molecule Lck inhibitors since 2005.
- To analyze Lck inhibitors from a structural perspective.
- To provide an overview of the current landscape of Lck inhibitor research.
Main Methods:
- Systematic review of patents and scientific literature.
- Analysis of small molecule kinase inhibitors of Lck.
- Structural analysis of identified inhibitors.
Main Results:
- Overview of structural classes and binding modes of Lck inhibitors.
- Identification of major research players in Lck inhibitor development.
- Insight into the current status and challenges in the field.
Conclusions:
- The development of potent and orally active Lck inhibitors is a significant research focus.
- Despite considerable efforts, a highly selective and potent Lck inhibitor for immunosuppression is yet to be identified.
- The search for effective Lck inhibitors continues to be an active area of investigation.
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