Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors
Xiaohua Huang1, Gerald W Shipps1, Cliff C Cheng1
1Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
ACS Medicinal Chemistry Letters
|June 6, 2014
Summary
Researchers discovered novel non-ATP-competitive inhibitors for MAP kinase-activated protein kinase 2 (MK2) using a furan-2-carboxyamide scaffold. These potent and selective inhibitors show promise for targeting the enzyme
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Pharmacology
Background:
- Mitogen-activated protein kinase 2 (MK2) is a key regulator in inflammatory pathways.
- Developing selective MK2 inhibitors is crucial for therapeutic intervention in inflammatory diseases.
Purpose of the Study:
- To discover and optimize novel non-ATP-competitive inhibitors of MK2.
- To characterize the binding mode and properties of these novel inhibitors.
Main Methods:
- High-throughput screening utilizing affinity selection-mass spectrometry (AS-MS) and the Automated Ligand Identification System (ALIS).
- Lead optimization through medicinal chemistry efforts.
- Biophysical and biochemical assays to confirm binding mode and assess potency and selectivity.
Main Results:
- Discovery of a novel series of non-ATP-competitive MK2 inhibitors based on a furan-2-carboxyamide scaffold.
- Optimization yielded leadlike compounds with improved biochemical and cellular potency.
- Inhibitors demonstrated excellent kinase selectivity and favorable in vitro pharmacokinetic properties.
- Confirmed a unique non-ATP-competitive binding mode, targeting the outside ATP pocket.
Conclusions:
- Highly selective MK2 inhibitors are feasible by targeting the outside ATP pocket.
- The identified furan-2-carboxyamide scaffold represents a promising starting point for developing novel MK2-targeted therapeutics.
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