3OY1

Highly Selective c-Jun N-Terminal Kinase (JNK) 2 and 3 Inhibitors with In Vitro CNS-like Pharmacokinetic Properties

Summary for 3OY1

• Entry DOI: 10.2210/pdb3oy1/pdb
• Descriptor: Mitogen-activated protein kinase 10, 5-[2-(cyclohexylamino)pyridin-4-yl]-4-naphthalen-2-yl-2-(tetrahydro-2H-pyran-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3 entities in total)
• Functional Keywords: kinase inhibitor, cns, selectivity, transferase, transherase-transferase inhibitor complex, transherase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P53779
• Total number of polymer chains: 1
• Total formula weight: 42268.94

Authors

Probst, G.D.,Bowers, S.,Sealy, J.M.,Truong, A.,Neitz, J.,Hom, R.K.,Galemmo Jr., R.A.,Konradi, A.W.,Sham, H.L.,Quincy, D.,Pan, H.,Yao, N. (deposition date: 2010-09-22, release date: 2011-08-17, Last modification date: 2024-02-21)

Primary citation

Probst, G.D.,Bowers, S.,Sealy, J.M.,Truong, A.P.,Hom, R.K.,Galemmo, R.A.,Konradi, A.W.,Sham, H.L.,Quincy, D.A.,Pan, H.,Yao, N.,Lin, M.,Toth, G.,Artis, D.R.,Zmolek, W.,Wong, K.,Qin, A.,Lorentzen, C.,Nakamura, D.F.,Quinn, K.P.,Sauer, J.M.,Powell, K.,Ruslim, L.,Wright, S.,Chereau, D.,Ren, Z.,Anderson, J.P.,Bard, F.,Yednock, T.A.,Griswold-Prenner, I.
Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.
Bioorg.Med.Chem.Lett., 21:315-319, 2011

PubMed Abstract: 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.

PubMed: 21112785
DOI: 10.1016/j.bmcl.2010.11.010

Experimental method

X-RAY DIFFRACTION (1.7 Å)