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

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

  • ACS Med Chem Lett. 2011 Jun 24;2(8):632-7. doi: 10.1021/ml200113y.
Xiaohua Huang 1,  Gerald W Shipps Jr 1,  Cliff C Cheng 1,  Peter Spacciapoli 1,  Xingmin Zhang 1,  Mark A McCoy 1,  Daniel F Wyss 1,  Xianshu Yang 1,  Abdelghani Achab 1,  Kyle Soucy 1,  Donna K Montavon 1,  Denise M Murphy 1,  Charles E Whitehurst 1
Affiliations

Affiliation

  • 1 Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
PMID: 24900358 DOI: 10.1021/ml200113y
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.

Keywords

1H/15N-HSQC (heteronuclear single quantum coherence); Automated Ligand Identification System (ALIS); Mitogen-activated protein kinase-activated protein kinase 2; non-ATP-competitive inhibitors; saturation-transfer-difference (STD) NMR.

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