PDBsum entry 4iva

Transferase/transferase inhibitor

PDB id: 4iva

Contents

Protein chain

292 a.a.

Ligands

1J5

Waters ×279

PDB id:

4iva

Name:

Transferase/transferase inhibitor

Title:

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

Structure:

Tyrosine-protein kinase jak2. Chain: a. Fragment: unp residues 833-1132. Synonym: janus kinase 2, jak-2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.50Å R-factor: 0.176 R-free: 0.193

Authors:

C.Eigenbrot,S.Shia

Key ref:

M.Zak et al. (2013). 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. PubMed id: 23659214 DOI: 10.1021/jm4004895

Date:

22-Jan-13 Release date: 22-May-13

Protein chain

O60674  (JAK2_HUMAN) -  Tyrosine-protein kinase JAK2 from Homo sapiens

Seq: 1132 a.a.

Struc: 292 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1021/jm4004895

J Med Chem 56:4764-4785 (2013)

PubMed id: 23659214

Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2.

M.Zak, C.A.Hurley, S.I.Ward, P.Bergeron, K.Barrett, M.Balazs, W.S.Blair, R.Bull, P.Chakravarty, C.Chang, P.Crackett, G.Deshmukh, J.DeVoss, P.S.Dragovich, C.Eigenbrot, C.Ellwood, S.Gaines, N.Ghilardi, P.Gibbons, S.Gradl, P.Gribling, C.Hamman, E.Harstad, P.Hewitt, A.Johnson, T.Johnson, J.R.Kenny, M.F.Koehler, P.Bir Kohli, S.Labadie, W.P.Lee, J.Liao, M.Liimatta, R.Mendonca, R.Narukulla, R.Pulk, A.Reeve, S.Savage, S.Shia, M.Steffek, S.Ubhayakar, A.van Abbema, I.Aliagas, B.Avitabile-Woo, Y.Xiao, J.Yang, J.J.Kulagowski.

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.