Structure Report for: 6M08

Hu, H.C., Xu, Y.C.

Title: Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach
Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H and Xu Y <3 more author(s)> Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H, Huang R, Li M, Shen J, Xu Y (- 3)
Ref: Journal of Medicinal Chemistry, 63:7052, 2020 : PubMed
Abstract


ESTHER: Huang_2020_J.Med.Chem_63_7052
PubMedSearch: Huang 2020 J.Med.Chem 63 7052
PubMedID: 32459096
Inhibitor(s) related to this paper: 6M08-BWL, 6M07-BWO, 6M06-BWF

Abstract

Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.