Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting

• Published in: Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (18), p.4229-4237
• Main Authors: Forster, Michael, Gehringer, Matthias, Laufer, Stefan A.
• Format: Article
• Language: English
• Subjects: Chemical probes; Covalent inhibitors; Covalent-reversible inhibitors; Cysteine - antagonists & inhibitors; Cysteine - metabolism; Humans; Inflammation; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoform selectivity; Janus kinase 3; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - metabolism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.07.079

[Display omitted] •Highly isoform-selective JAK3 inhibition was achieved by covalent targeting of Cys909.•Covalent-reversible targeting of Cys909 has been validated.•Selective JAK3 inhibition effectively suppresses downstream signaling.•A highly isoform-selective JAK3 inhibitor is now in phase II clinical studies. Janus kinases (JAKs) are a family of four cytosolic protein kinases with a high degree of structural similarity. Due to its very restricted role in immune regulation, JAK3 was promoted as an excellent target for immunosuppression for more than a decade, but clinical validation of this concept is still elusive. During the last years, speculation arose that kinase activity of JAK1, which cooperates with JAK3 in cytokine receptor signaling, may have a dominant role over the one of JAK3. Until recently, however, this issue could not be appropriately addressed due to a lack of highly isoform-selective tool compounds. With the recent resurgence of covalent drugs, targeting of a specific cysteine that distinguishes JAK3 from other JAK family members became an attractive design option. By applying this strategy, a set of JAK3 inhibitors with excellent selectivity against other JAK isoforms and the kinome was developed during the last three years and used to decipher JAK3-dependent signaling. The data obtained with these tool compounds demonstrates that selective JAK3 inhibition is sufficient to block downstream signaling. Since one of these inhibitors is currently under evaluation in phase II clinical studies against several inflammatory disorders, it will soon become apparent whether selective JAK3 inhibition translates into clinical efficacy.