Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors

Jingrong Cao; Huai Gao; Guy Bemis; Francesco Salituro; Mark Ledeboer; Edmund Harrington; Susanne Wilke; Paul Taslimi; S Pazhanisamy; Xiaoling Xie; Marc Jacobs; Jeremy Green

doi:10.1016/j.bmcl.2009.03.043

Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors

Bioorg Med Chem Lett. 2009 May 15;19(10):2891-5. doi: 10.1016/j.bmcl.2009.03.043. Epub 2009 Mar 17.

Authors

Jingrong Cao¹, Huai Gao, Guy Bemis, Francesco Salituro, Mark Ledeboer, Edmund Harrington, Susanne Wilke, Paul Taslimi, S Pazhanisamy, Xiaoling Xie, Marc Jacobs, Jeremy Green

Affiliation

¹ Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, United States.

PMID: 19361991
DOI: 10.1016/j.bmcl.2009.03.043

Abstract

A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.

MeSH terms

Catalytic Domain
Crystallography, X-Ray
Drug Design
Isatin / chemical synthesis
Isatin / chemistry*
Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 10 / metabolism
Oximes / chemical synthesis
Oximes / chemistry*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Structure-Activity Relationship

Substances

Oximes
Protein Kinase Inhibitors
Isatin
Mitogen-Activated Protein Kinase 10