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6DBN

Jak1 with compound 23

Summary for 6DBN
Entry DOI10.2210/pdb6dbn/pdb
DescriptorTyrosine-protein kinase JAK1, [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone (3 entities in total)
Functional Keywordskinase, transferase
Biological sourceHomo sapiens (Human)
Total number of polymer chains1
Total formula weight36806.87
Authors
Vajdos, F.F. (deposition date: 2018-05-03, release date: 2018-08-29, Last modification date: 2024-10-23)
Primary citationFensome, A.,Ambler, C.M.,Arnold, E.,Banker, M.E.,Brown, M.F.,Chrencik, J.,Clark, J.D.,Dowty, M.E.,Efremov, I.V.,Flick, A.,Gerstenberger, B.S.,Gopalsamy, A.,Hayward, M.M.,Hegen, M.,Hollingshead, B.D.,Jussif, J.,Knafels, J.D.,Limburg, D.C.,Lin, D.,Lin, T.H.,Pierce, B.S.,Saiah, E.,Sharma, R.,Symanowicz, P.T.,Telliez, J.B.,Trujillo, J.I.,Vajdos, F.F.,Vincent, F.,Wan, Z.K.,Xing, L.,Yang, X.,Yang, X.,Zhang, L.
Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841).
J. Med. Chem., 61:8597-8612, 2018
Cited by
PubMed Abstract: Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
PubMed: 30113844
DOI: 10.1021/acs.jmedchem.8b00917
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.48 Å)
Structure validation

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