6DBK

Tyk2 with compound 8

6DBK の概要

• エントリーDOI: 10.2210/pdb6dbk/pdb
• 分子名称: Non-receptor tyrosine-protein kinase TYK2, 4-({4-[(1S,4S)-5-(cyanoacetyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide (3 entities in total)
• 機能のキーワード: kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36956.02

構造登録者

Vajdos, F.F. (登録日: 2018-05-03, 公開日: 2018-08-29, 最終更新日: 2024-10-30)

主引用文献

Fensome, 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

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

実験手法

X-RAY DIFFRACTION (2 Å)