4E6D: Jak2 Kinase (Jh1 Domain) Triple Mutant In Complex With Compound 7

Citation:
Abstract
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
PDB ID: 4E6DDownload
MMDB ID: 100144
PDB Deposition Date: 2012/3/15
Updated in MMDB: 2012/07
Experimental Method:
x-ray diffraction
Resolution: 2.22  Å
Source Organism:
Similar Structures:
Biological Unit for 4E6D: dimeric; determined by author
Molecular Components in 4E6D
Label Count Molecule
Proteins (2 molecules)
2
Tyrosine-protein Kinase Jak2(Gene symbol: JAK2)
Molecule annotation
Chemicals (3 molecules)
1
2
2
1
* Click molecule labels to explore molecular sequence information.

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