4PRJ: Aurora A Kinase Domain With Compound 2 (n-[1-(3-cyanobenzyl)-1h- Pyrazol-4-yl]-6-(1h-pyrazol-4-yl)-1h-indazole-3-carboxamide)

Citation:
Abstract
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
PDB ID: 4PRJDownload
MMDB ID: 121223
PDB Deposition Date: 2014/3/5
Updated in MMDB: 2014/07
Experimental Method:
x-ray diffraction
Resolution: 2.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4PRJ: monomeric; determined by author and by software (PISA)
Molecular Components in 4PRJ
Label Count Molecule
Protein (1 molecule)
1
Aurora Kinase a(Gene symbol: AURKA)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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