4E73

Crystal structure of JNK1beta-JIP in complex with an azaquinolone inhbitor

Summary for 4E73

• Entry DOI: 10.2210/pdb4e73/pdb
• Related: 1UKH
• Descriptor: Mitogen-activated protein kinase 8, C-Jun-amino-terminal kinase-interacting protein 1, methyl 3-(4-{[(1R,2S,3S,5S,7s)-5-aminotricyclo[3.3.1.1~3,7~]dec-2-yl]carbamoyl}benzyl)-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridine-2-carboxylate, ... (4 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P45983; Cytoplasm (By similarity): Q9UQF2
• Total number of polymer chains: 2
• Total formula weight: 44468.45

Authors

Lukacs, C.M.,Janson, C.A. (deposition date: 2012-03-16, release date: 2013-05-29, Last modification date: 2023-09-13)

Primary citation

Haynes, N.E.,Scott, N.R.,Chen, L.C.,Janson, C.A.,Li, J.K.,Lukacs, C.M.,Railkar, A.,Tozzo, E.,Whittard, T.,Brown, N.F.,Cheung, A.W.
Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor.
ACS Med Chem Lett, 3:764-768, 2012

PubMed Abstract: 3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure-activity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-α challenge models.

PubMed: 24900545
DOI: 10.1021/ml300175c

Experimental method

X-RAY DIFFRACTION (2.27 Å)