Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.

Autor: Burke JR; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA. james.burke@bms.com., Cheng L; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Gillooly KM; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Strnad J; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Zupa-Fernandez A; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Catlett IM; Innovative Medicines Development, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Zhang Y; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Heimrich EM; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., McIntyre KW; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Cunningham MD; Translational Medicine, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Carman JA; Translational Medicine, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Zhou X; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Banas D; Translational Medicine, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Chaudhry C; Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Li S; Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., D'Arienzo C; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Chimalakonda A; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Yang X; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Xie JH; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Pang J; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Zhao Q; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Rose SM; Innovative Medicines Development, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Huang J; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Moslin RM; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Wrobleski ST; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Weinstein DS; Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA., Salter-Cid LM; Immunosciences Discovery Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2019 Jul 24; Vol. 11 (502).
DOI: 10.1126/scitranslmed.aaw1736
Abstrakt: 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 autoimmune diseases 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 responses in human T H 17, T H 1, B cells, and myeloid cells integral to autoimmunity were 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 autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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