Open AccessDiscovery of a Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase with Oral Anti-Inflammatory Activity
Author(s) -
Mark S. Tichenor,
John J. M. Wiener,
Navin Rao,
Charlotte Pooley Deckhut,
J. Kent Barbay,
K. D. Kreutter,
Genesis M. Bacani,
Jianmei Wei,
Leon Chang,
Heather E. Murrey,
Weixue Wang,
Kay Ahn,
Michael Huber,
Elizabeth Rex,
Kevin J. Coe,
Jiejun Wu,
Mark Seierstad,
Scott D. Bembenek,
Kristi Leonard,
Alec D. Lebsack,
Jennifer D. Venable,
James P. Edwards
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00044
Subject(s) - bruton's tyrosine kinase , ibrutinib , tyrosine kinase , chemistry , in vivo , covalent bond , tyrosine , cancer research , pharmacology , biochemistry , medicine , immunology , biology , signal transduction , leukemia , chronic lymphocytic leukemia , microbiology and biotechnology , organic chemistry
Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3 H -1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.