6X8E

Crystal structure of JAK2 with Compound 11

Summary for 6X8E

• Entry DOI: 10.2210/pdb6x8e/pdb
• Descriptor: Tyrosine-protein kinase JAK2, [3-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1H-pyrazol-1-yl}-1-(2,2,2-trifluoroethyl)azetidin-3-yl]acetonitrile (3 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70950.19

Authors

Vajdos, F.F.,Knafels, J.D. (deposition date: 2020-06-01, release date: 2020-11-25, Last modification date: 2024-10-16)

Primary citation

Gerstenberger, B.S.,Ambler, C.,Arnold, E.P.,Banker, M.E.,Brown, M.F.,Clark, J.D.,Dermenci, A.,Dowty, M.E.,Fensome, A.,Fish, S.,Hayward, M.M.,Hegen, M.,Hollingshead, B.D.,Knafels, J.D.,Lin, D.W.,Lin, T.H.,Owen, D.R.,Saiah, E.,Sharma, R.,Vajdos, F.F.,Xing, L.,Yang, X.,Yang, X.,Wright, S.W.
Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.
J.Med.Chem., 63:13561-13577, 2020

PubMed Abstract: Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 ().

PubMed: 32787094
DOI: 10.1021/acs.jmedchem.0c00948

Experimental method

X-RAY DIFFRACTION (1.75 Å)