TY - JOUR
T1 - KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation
AU - Wunderle, Veronika
AU - Wilhelm, Thomas
AU - Boukeileh, Shatha
AU - Goßen, Jonas
AU - Margreiter, Michael A.
AU - Sakurov, Roman
AU - Capellmann, Sandro
AU - Schwoerer, Maike
AU - Ahmed, Nabil
AU - Bronneberg, Gina
AU - Arock, Michel
AU - Martin, Christian
AU - Schubert, Thomas
AU - Levi-Schaffer, Francesca
AU - Rossetti, Giulia
AU - Tirosh, Boaz
AU - Huber, Michael
N1 - Publisher Copyright:
© 2024 The Author(s). European Journal of Immunology published by Wiley-VCH GmbH.
PY - 2024
Y1 - 2024
N2 - Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN. KIRA6 attenuates Ag-stimulated early signaling and effector functions such as degranulation and proinflammatory cytokine production/secretion in murine bone marrow-derived MCs. Moreover, Ag-triggered bronchoconstriction in an ex vivo model and IgE-mediated stimulation of human MCs were repressed by KIRA6. The interaction of KIRA6 with three MC-relevant tyrosine kinases, LYN, FYN, and KIT, and the potential of KIRA6 structure as a pharmacophore for the development of respective single-, dual-, or triple-specificity inhibitors, was evaluated by homology modeling and molecular dynamics simulations. We found that KIRA6 particularly strongly binds the inactive state of LYN, FYN, and KIT with comparable affinities. In conclusion, our data suggest that the chemical structure of KIRA6 as a pharmacophore can be further developed to obtain an effective MC stabilizer.
AB - Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN. KIRA6 attenuates Ag-stimulated early signaling and effector functions such as degranulation and proinflammatory cytokine production/secretion in murine bone marrow-derived MCs. Moreover, Ag-triggered bronchoconstriction in an ex vivo model and IgE-mediated stimulation of human MCs were repressed by KIRA6. The interaction of KIRA6 with three MC-relevant tyrosine kinases, LYN, FYN, and KIT, and the potential of KIRA6 structure as a pharmacophore for the development of respective single-, dual-, or triple-specificity inhibitors, was evaluated by homology modeling and molecular dynamics simulations. We found that KIRA6 particularly strongly binds the inactive state of LYN, FYN, and KIT with comparable affinities. In conclusion, our data suggest that the chemical structure of KIRA6 as a pharmacophore can be further developed to obtain an effective MC stabilizer.
KW - allergy treatment
KW - IgE
KW - inflammation
KW - mast cells
KW - signal transduction
UR - http://www.scopus.com/inward/record.url?scp=85212130142&partnerID=8YFLogxK
U2 - 10.1002/eji.202451348
DO - 10.1002/eji.202451348
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C2 - 39676406
AN - SCOPUS:85212130142
SN - 0014-2980
JO - European Journal of Immunology
JF - European Journal of Immunology
ER -