Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)

Frank Lovering; Steve Kirincich; Weiheng Wang; Kerry Combs; Lynn Resnick; Joan E Sabalski; John Butera; Julie Liu; Kevin Parris; J B Telliez

doi:10.1016/j.bmc.2009.03.041

Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)

Bioorg Med Chem. 2009 May 1;17(9):3342-51. doi: 10.1016/j.bmc.2009.03.041. Epub 2009 Mar 26.

Authors

Frank Lovering¹, Steve Kirincich, Weiheng Wang, Kerry Combs, Lynn Resnick, Joan E Sabalski, John Butera, Julie Liu, Kevin Parris, J B Telliez

Affiliation

¹ Chemical Sciences, Wyeth Research, Cambridge, MA 02140, USA. flovering@wyeth.com

PMID: 19364658
DOI: 10.1016/j.bmc.2009.03.041

Abstract

A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Cell Line, Tumor
Cyclobutanes / chemistry*
Cyclobutanes / pharmacology*
Drug Design
Humans
Inhibitory Concentration 50
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 1 / metabolism
Models, Molecular
Monocytes / cytology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Transport
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / biosynthesis

Substances

Cyclobutanes
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 1
squaric acid