10PISummary for 10PI
| Entry DOI | 10.2210/pdb10pi/pdb |
| Descriptor | Tyrosine-protein kinase JAK1, 1,2-ETHANEDIOL, 4-{3-(cyanomethyl)-3-[(4M)-3',5'-dimethyl-1H,1'H-[4,4'-bipyrazol]-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(2S)-1,1,1-trifluoropropan-2-yl]benzamide, ... (5 entities in total) |
| Functional Keywords | inhibitor, kinase, complex, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 70704.79 |
| Authors | |
| Primary citation | Zhuo, J.,Li, Y.L.,Qian, D.Q.,Burns, D.M.,Mei, S.,Rafalski, M.,Xu, M.,Cao, G.,Pan, Y.,Jia, Z.,Jalluri, R.,Epling, L.B.,Fenalti, G.,Deller, M.C.,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. Discovery of the Orally Bioavailable Isoform Selective Janus Kinase 1 (JAK1) Compound Povorcitinib (INCB054707) for the Treatment of Inflammatory and Autoimmune Diseases. J.Med.Chem., 2026 Cited by PubMed Abstract: 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 , which selectively inhibited JAK1 over JAK2. Iterative breakthroughs led to the discovery of povorcitinib (INCB054707, ), 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. PubMed: 42202255DOI: 10.1021/acs.jmedchem.5c03753 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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