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Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors.

ABSTRACT: A novel series of non-ATP-competitive MK2 inhibitors based on a furan-2-carboxyamide scaffold was discovered through high-throughput screening using the affinity selection-mass spectrometry-based Automated Ligand Identification System platform. Medicinal chemistry efforts optimized the initial screening hit to leadlike compounds with significant improvements in biochemical and cellular potencies, while maintaining excellent kinase selectivity and in vitro pharmacokinetic properties. Biophysical and biochemical studies confirmed the unique non-ATP-competitive binding mode of this series and suggested that highly selective inhibitors of MK2 should be feasible by targeting the outside ATP pocket.

SUBMITTER: Huang X

PROVIDER: S-EPMC4017987 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors.

Huang Xiaohua X Shipps Gerald W GW Cheng Cliff C CC Spacciapoli Peter P Zhang Xingmin X McCoy Mark A MA Wyss Daniel F DF Yang Xianshu X Achab Abdelghani A Soucy Kyle K Montavon Donna K DK Murphy Denise M DM Whitehurst Charles E CE

ACS medicinal chemistry letters 20110624 8

A novel series of non-ATP-competitive MK2 inhibitors based on a furan-2-carboxyamide scaffold was discovered through high-throughput screening using the affinity selection-mass spectrometry-based Automated Ligand Identification System platform. Medicinal chemistry efforts optimized the initial screening hit to leadlike compounds with significant improvements in biochemical and cellular potencies, while maintaining excellent kinase selectivity and in vitro pharmacokinetic properties. Biophysical ...[more]

PMID: 24900358

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