Document Report Card

ID: ALA3351787

Journal: J Med Chem

Title: Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.

Authors: Cocco M, Garella D, Di Stilo A, Borretto E, Stevanato L, Giorgis M, Marini E, Fantozzi R, Miglio G, Bertinaria M.

Abstract: Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure-activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.

CiteXplore: 25418070

DOI: 10.1021/jm501072b