title: 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.
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Spacciapoli
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Xingmin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCoy
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Xianshu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Achab
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Soucy
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Montavon
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Murphy
authors.affiliation: Merck Research Laboratories , 320 Bent Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Whitehurst
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