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Title: Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

Journal Article · · Journal of Biological Chemistry
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  1. AbbVie Bioresearch Center, Worcester, MA (United States)
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The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. In this paper, we have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nM) inhibit Jak3 activity in cell-based assays. Finally, these results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.

Research Organization:
AbbVie Bioresearch Center, Worcester, MA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); AbbVie (United States); Hauptman-Woodward Medical Research Inst. (United States)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1171860
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 8; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 75 works
Citation information provided by
Web of Science

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Cited By (16)

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases journal January 2018
Systematic Studies on the Protocol and Criteria for Selecting a Covalent Docking Tool journal June 2019
Evaluation of JAK3 Biology in Autoimmune Disease Using a Highly Selective, Irreversible JAK3 Inhibitor journal February 2017
Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis journal March 2018
Merits and Pitfalls in the Characterization of Covalent Inhibitors of Bruton’s Tyrosine Kinase journal July 2018
Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling journal March 2016
The Cysteinome of Protein Kinases as a Target in Drug Development journal February 2018
Controlling cellular distribution of drugs with permeability modifying moieties journal January 2019
Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors journal February 2018
Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis: Highly Selective JAK3 Inhibitor journal September 2017
Erratum: Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition journal December 2017
JAK inhibition as a therapeutic strategy for immune and inflammatory diseases journal November 2017
Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma journal February 2018
Selective and reversible modification of kinase cysteines with chlorofluoroacetamides journal January 2019
JAK selectivity for inflammatory bowel disease treatment: does it clinically matter? journal June 2019
Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile janus kinase inhibition journal January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Cytokine
Drug Discovery
Enzyme Inhibitor
Enzyme Kinetics
Janus Kinase (JAK)
Jak3
Covalent Inhibitor
Tyrosine Kinase