Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain
2019
TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common
autoimmunediseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of
autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and
functional responsesin human TH17, TH1, B cells, and myeloid cells integral to
autoimmunitywere blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple
autoimmunepathways, in murine models of
lupus nephritisand inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.
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