c-Kit/Lyn/Fyn tyrosine kinases (mast cell/microglia)

Class

Tyrosine-kinase inhibitor

c-Kit is a receptor tyrosine kinase activated by stem cell factor; it governs the survival, proliferation, and maturation of mast cells, the immune cells responsible for releasing histamine and other mediators during allergic and inflammatory responses. Lyn and Fyn are non-receptor tyrosine kinases of the Src family that act just inside the cell membrane, relaying signals from surface receptors such as the IgE receptor on mast cells and from activating receptors on microglia, the resident immune cells of the brain. Together, this trio of kinases sits at the crossroads of two related processes: the buildup of mast cell populations (via c-Kit) and their moment-to-moment activation (via Lyn and Fyn), as well as the inflammatory activity of microglia in the central nervous system. Inhibiting these kinases can reduce mast cell numbers and dampen their release of inflammatory mediators, which is relevant to mast-cell-driven diseases and chronic allergic or inflammatory conditions. Because Lyn and Fyn also participate in microglial signaling, the same inhibitory approach has been explored for neuroinflammatory and neurodegenerative conditions where overactive microglia contribute to tissue damage. A single small molecule capable of engaging all three kinases can therefore address both peripheral immune and central nervous system components of disease within one mechanism.