PDB 3OY1 deposited: 2010-09-22 modified: 2011-08-17
Title Highly Selective c-Jun N-Terminal Kinase (JNK) 2 and 3 Inhibitors with In Vitro CNS-like Pharmacokinetic Properties
Authors Anderson, J.P., Artis, D.R., Bard, F., Bowers, S., Chereau, D., Galemmo, R.A., Griswold-Prenner, I., Hom, R.K., Konradi, A.W., Lin, M., Lorentzen, C., Nakamura, D.F., Pan, H., Powell, K., Probst, G.D., Qin, A., Quincy, D.A., Quinn, K.P., Ren, Z., Ruslim, L., Sauer, J.M., Sealy, J.M., Sham, H.L., Toth, G., Truong, A.P., Wong, K., Wright, S., Yao, N., Yednock, T.A., Zmolek, W.
Structure factors resolution 1.7 rfactor 0.258 rfree 0.299
DPI 0.54 theoretical min: 0.16

In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.

Bioorg.Med.Chem.Lett. 2011 Jan; 21(1):315-319 doi:10.1016/j.bmcl.2010.11.010

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1641539
PubMed 21112785 BMCLE8
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3OY1/0 3OY1 0 monomer 0 1 1 2588