4I5C

The Jak1 kinase domain in complex with inhibitor

Summary for 4I5C

• Entry DOI: 10.2210/pdb4i5c/pdb
• Descriptor: Tyrosine-protein kinase JAK1, 3-oxo-3-[(3R)-3-(pyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridin-1(6H)-yl)piperidin-1-yl]propanenitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein: P23458
• Total number of polymer chains: 2
• Total formula weight: 70360.11

Authors

Fong, R.,Lupardus, P.J. (deposition date: 2012-11-28, release date: 2013-05-22, Last modification date: 2024-10-30)

Primary citation

Hurley, C.A.,Blair, W.S.,Bull, R.J.,Chang, C.,Crackett, P.H.,Deshmukh, G.,Dyke, H.J.,Fong, R.,Ghilardi, N.,Gibbons, P.,Hewitt, P.R.,Johnson, A.,Johnson, T.,Kenny, J.R.,Kohli, P.B.,Kulagowski, J.J.,Liimatta, M.,Lupardus, P.J.,Maxey, R.J.,Mendonca, R.,Narukulla, R.,Pulk, R.,Ubhayakar, S.,van Abbema, A.,Ward, S.I.,Waszkowycz, B.,Zak, M.
Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.
Bioorg.Med.Chem.Lett., 23:3592-3598, 2013

PubMed Abstract: The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

PubMed: 23642482
DOI: 10.1016/j.bmcl.2013.04.018

Experimental method

X-RAY DIFFRACTION (2.1 Å)