Open AccessDevelopment of Selective Covalent Janus Kinase 3 Inhibitors
Author(s) -
Tan Li,
Koshi Akahane,
Randall McNally,
Kathleen M. S. E. Reyskens,
Scott B. Ficarro,
Suhu Liu,
Grit S. Herter-Sprie,
Shohei Koyama,
Michael J. Pattison,
Katherine Labella,
Liv Johannessen,
Esra A. Akbay,
Kwok-Kin Wong,
David A. Frank,
Jarrod A. Marto,
Thomas Look,
J. Simon C. Arthur,
Michael J. Eck,
Nathanael S. Gray
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b00710
Subject(s) - chemistry , janus kinase , kinase , effector , covalent bond , stat protein , drug discovery , innate immune system , immune system , signal transduction , biochemistry , computational biology , microbiology and biotechnology , stat3 , biology , receptor , immunology , organic chemistry
The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.