4FK6

JAK1 kinase (JH1 domain) in complex with compound 72

Summary for 4FK6

• Entry DOI: 10.2210/pdb4fk6/pdb
• Related: 4E4L 4E4N
• Descriptor: Tyrosine-protein kinase JAK1, N-({1-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl}methyl)methanesulfonamide (3 entities in total)
• Functional Keywords: protein kinase, phospho transfer, phospho tyrosine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein: P23458
• Total number of polymer chains: 2
• Total formula weight: 70212.08

Authors

Eigenbrot, C.,Steffek, M. (deposition date: 2012-06-12, release date: 2012-11-07, Last modification date: 2024-10-09)

Primary citation

Labadie, S.,Dragovich, P.S.,Barrett, K.,Blair, W.S.,Bergeron, P.,Chang, C.,Deshmukh, G.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Hurley, C.A.,Johnson, A.,Kenny, J.R.,Kohli, P.B.,Kulagowski, J.J.,Liimatta, M.,Lupardus, P.J.,Mendonca, R.,Murray, J.M.,Pulk, R.,Shia, S.,Steffek, M.,Ubhayakar, S.,Ultsch, M.,van Abbema, A.,Ward, S.,Zak, M.
Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.
Bioorg.Med.Chem.Lett., 22:7627-7633, 2012

PubMed Abstract: Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.

PubMed: 23107482
DOI: 10.1016/j.bmcl.2012.10.008

Experimental method

X-RAY DIFFRACTION (2.2 Å)