Journal Article

FZJ-2026-03227

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE‐mediated Activation

Wunderle, V. ; Wilhelm, T. ; Boukeileh, S. ; Goßen, J.FZJ* ; Margreiter, M. A. ; Sakurov, R. ; Capellmann, S. ; Schwoerer, M. ; Ahmed, N. ; Bronneberg, G. ; Arock, M. ; Martin, C. ; Schubert, T. ; Levi-Schaffer, F. ; Rossetti, G.FZJ* ; Tirosh, B. ; Huber, M. (Corresponding author)

2025
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/eji.202451348  doi:10.34734/FZJ-2026-03227

Abstract: 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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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