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

Publication ,  Journal Article
Burke, JR; Cheng, L; Gillooly, KM; Strnad, J; Zupa-Fernandez, A; Catlett, IM; Zhang, Y; Heimrich, EM; McIntyre, KW; Cunningham, MD; Carman, JA ...
Published in: Science translational medicine
July 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 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 TH17, TH1, 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.

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Published In

Science translational medicine

DOI

EISSN

1946-6242

ISSN

1946-6234

Publication Date

July 2019

Volume

11

Issue

502

Start / End Page

eaaw1736

Related Subject Headings

  • TYK2 Kinase
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Mice, SCID
  • Mice, Inbred C57BL
  • Mice
  • Interferon alpha-2
  • Humans
  • Heterocyclic Compounds
  • Healthy Volunteers
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Burke, J. R., Cheng, L., Gillooly, K. M., Strnad, J., Zupa-Fernandez, A., Catlett, I. M., … Salter-Cid, L. M. (2019). Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Science Translational Medicine, 11(502), eaaw1736. https://doi.org/10.1126/scitranslmed.aaw1736
Burke, James R., Lihong Cheng, Kathleen M. Gillooly, Joann Strnad, Adriana Zupa-Fernandez, Ian M. Catlett, Yifan Zhang, et al. “Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.Science Translational Medicine 11, no. 502 (July 2019): eaaw1736. https://doi.org/10.1126/scitranslmed.aaw1736.
Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Science translational medicine. 2019 Jul;11(502):eaaw1736.
Burke, James R., et al. “Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.Science Translational Medicine, vol. 11, no. 502, July 2019, p. eaaw1736. Epmc, doi:10.1126/scitranslmed.aaw1736.
Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, Zhang Y, Heimrich EM, McIntyre KW, Cunningham MD, Carman JA, Zhou X, Banas D, Chaudhry C, Li S, D’Arienzo C, Chimalakonda A, Yang X, Xie JH, Pang J, Zhao Q, Rose SM, Huang J, Moslin RM, Wrobleski ST, Weinstein DS, Salter-Cid LM. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Science translational medicine. 2019 Jul;11(502):eaaw1736.

Published In

Science translational medicine

DOI

EISSN

1946-6242

ISSN

1946-6234

Publication Date

July 2019

Volume

11

Issue

502

Start / End Page

eaaw1736

Related Subject Headings

  • TYK2 Kinase
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Mice, SCID
  • Mice, Inbred C57BL
  • Mice
  • Interferon alpha-2
  • Humans
  • Heterocyclic Compounds
  • Healthy Volunteers