PDBsum entry 4i5c

Transferase

PDB id: 4i5c

Contents

Protein chains

281 a.a.

293 a.a.

Ligands

C5I ×2

EDO ×4

Waters ×299

PDB id:

4i5c

Name:

Transferase

Title:

The jak1 kinase domain in complex with inhibitor

Structure:

Tyrosine-protein kinase jak1. Chain: a, b. Fragment: protein kinase 2 domain residues 854-1154. Synonym: janus kinase 1, jak-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak1, jak1a, jak1b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.10Å R-factor: 0.193 R-free: 0.245

Authors:

R.Fong,P.J.Lupardus

Key ref:

C.A.Hurley et al. (2013). Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. Bioorg Med Chem Lett, 23, 3592-3598. PubMed id: 23642482 DOI: 10.1016/j.bmcl.2013.04.018

Date:

28-Nov-12 Release date: 22-May-13

Protein chain

P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1 from Homo sapiens

Seq: 1154 a.a.

Struc: 281 a.a.

Protein chain

P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1 from Homo sapiens

Seq: 1154 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2013.04.018

Bioorg Med Chem Lett 23:3592-3598 (2013)

PubMed id: 23642482

Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.

C.A.Hurley, W.S.Blair, R.J.Bull, C.Chang, P.H.Crackett, G.Deshmukh, H.J.Dyke, R.Fong, N.Ghilardi, P.Gibbons, P.R.Hewitt, A.Johnson, T.Johnson, J.R.Kenny, P.B.Kohli, J.J.Kulagowski, M.Liimatta, P.J.Lupardus, R.J.Maxey, R.Mendonca, R.Narukulla, R.Pulk, S.Ubhayakar, A.van Abbema, S.I.Ward, B.Waszkowycz, M.Zak.

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).