8S85

Crystal structure of JAK1 JH1 domain in complex with an inhibitor

This is a non-PDB format compatible entry.

Summary for 8S85

• Entry DOI: 10.2210/pdb8s85/pdb
• Descriptor: Tyrosine-protein kinase JAK1, ~{N}-(2-ethylphenyl)-~{N},1-dimethyl-imidazo[4,5-c]pyridin-6-amine, SODIUM ION, ... (4 entities in total)
• Functional Keywords: kinase, jak1, inhibitor, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70094.84

Authors

Flower, T.F.,Lopez-Ramos, M.,Geney, R.,Jestel, A. (deposition date: 2024-03-05, release date: 2024-11-06)

Primary citation

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.
Design of a potent and selective dual JAK1/TYK2 inhibitor.
Bioorg.Med.Chem., 114:117932-117932, 2024

PubMed Abstract: Janus 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 T1 and T17 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.

PubMed: 39447537
DOI: 10.1016/j.bmc.2024.117932

Experimental method

X-RAY DIFFRACTION (1.75 Å)