8s85
Crystal structure of JAK1 JH1 domain in complex with an inhibitor
Structural highlights
FunctionJAK1_HUMAN Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. Publication Abstract from PubMedJanus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T(H)1 and T(H)17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model. Design of a potent and selective dual JAK1/TYK2 inhibitor.,Mammoliti O, Menet C, Cottereaux C, Blanc J, De Blieck A, Coti G, Geney R, Oste L, Ostyn K, Palisse A, Quinton E, Schmitt B, Borgonovi M, Parent I, Jagerschmidt C, De Vos S, Vayssiere B, Lopez-Ramos M, Shoji K, Brys R, Amantini D, Galien R, Joannesse C Bioorg Med Chem. 2024 Nov 15;114:117932. doi: 10.1016/j.bmc.2024.117932. Epub , 2024 Sep 30. PMID:39447537[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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