4IVA

JAK2 kinase (JH1 domain) in complex with the inhibitor TRANS-4-[(8AS)-2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(8AH)-YL]CYCLOHEXANECARBONITRILE

Summary for 4IVA

• Entry DOI: 10.2210/pdb4iva/pdb
• Related: 4IVB 4IVC 4IVD
• Descriptor: Tyrosine-protein kinase JAK2, trans-4-{2-[(1R)-1-hydroxyethyl]imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl}cyclohexanecarbonitrile (3 entities in total)
• Functional Keywords: protein kinase, phosphotransfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• Total number of polymer chains: 1
• Total formula weight: 35651.49

Authors

Eigenbrot, C.,Shia, S. (deposition date: 2013-01-22, release date: 2013-05-22, Last modification date: 2023-12-06)

Primary citation

Zak, M.,Hurley, C.A.,Ward, S.I.,Bergeron, P.,Barrett, K.,Balazs, M.,Blair, W.S.,Bull, R.,Chakravarty, P.,Chang, C.,Crackett, P.,Deshmukh, G.,Devoss, J.,Dragovich, P.S.,Eigenbrot, C.,Ellwood, C.,Gaines, S.,Ghilardi, N.,Gibbons, P.,Gradl, S.,Gribling, P.,Hamman, C.,Harstad, E.,Hewitt, P.,Johnson, A.,Johnson, T.,Kenny, J.R.,Koehler, M.F.,Bir Kohli, P.,Labadie, S.,Lee, W.P.,Liao, J.,Liimatta, M.,Mendonca, R.,Narukulla, R.,Pulk, R.,Reeve, A.,Savage, S.,Shia, S.,Steffek, M.,Ubhayakar, S.,van Abbema, A.,Aliagas, I.,Avitabile-Woo, B.,Xiao, Y.,Yang, J.,Kulagowski, J.J.
Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.
J.Med.Chem., 56:4764-4785, 2013

PubMed Abstract: Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

PubMed: 23659214
DOI: 10.1021/jm4004895

Experimental method

X-RAY DIFFRACTION (1.5 Å)