10pi

JAK1 kinase (JH1 domain) in complex with povorcitinib

spinqualitylabelsall models 10pi, resolution 1.54Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 10pi is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.54Å Ligands: A1C68, ACE, DMS, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function JAK1_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 PubMed Aberrant JAK2 signaling is a key driver in cancers such as myeloproliferative neoplasms (MPNs), whereas JAK1 acts as a central mediator of autoimmune and inflammatory diseases. Since JAK2 supports blood cell production, its inhibition can lead to anemia and other cytopenias, making selective JAK1 inhibition a potentially safer therapeutic strategy opposed to dual JAK1/JAK2 inhibition. We initially identified novel scaffold 9, which selectively inhibited JAK1 over JAK2. Iterative breakthroughs led to the discovery of povorcitinib (INCB054707, 22), which showed improved pharmacokinetics due to intramolecular hydrogen bonding of the amide moiety and a reduced ring size in the hinge binding motif. Protein crystallography suggested that JAK1 selectivity was conferred by the amide's alkyl group accessing a small lipophilic groove formed by the P-loop conformation of JAK1 that was distinct from JAK2. In murine arthritis models, povorcitinib demonstrated dose-dependent efficacy and reduced inflammatory signaling, supporting its therapeutic potential in immunological disorders. Discovery of the Orally Bioavailable Isoform Selective Janus Kinase 1 (JAK1) Compound Povorcitinib (INCB054707) for the Treatment of Inflammatory and Autoimmune Diseases.,Zhuo J, Li YL, Qian DQ, Burns DM, Mei S, Rafalski M, Xu M, Cao G, Pan Y, Jia Z, Jalluri R, Epling LB, Fenalti G, Deller MC, Procak J, Covington M, He X, Collins R, Stubbs M, Burke K, Oliver J, Margulis A, Boer J, Wynn R, Scherle P, Diamond S, Newton R, Zhang Y, Metcalf B, Yao W J Med Chem. 2026 May 27. doi: 10.1021/acs.jmedchem.5c03753. PMID:42202255 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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