221086-92-6Relevant academic research and scientific papers
Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease
Cocco, Mattia,Pellegrini, Carolina,Martínez-Banaclocha, Helios,Giorgis, Marta,Marini, Elisabetta,Costale, Annalisa,Miglio, Gianluca,Fornai, Matteo,Antonioli, Luca,López-Castejón, Gloria,Tapia-Abellán, Ana,Angosto, Diego,Hafner-Bratkovi?, Iva,Regazzoni, Luca,Blandizzi, Corrado,Pelegrín, Pablo,Bertinaria, Massimo
, p. 3656 - 3671 (2017)
Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.
Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties
Zambaldo,Daguer,Saarbach,Barluenga,Winssinger
supporting information, p. 1340 - 1351 (2016/07/21)
DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.
Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis
Cocco, Mattia,Garella, Davide,Di Stilo, Antonella,Borretto, Emily,Stevanato, Livio,Giorgis, Marta,Marini, Elisabetta,Fantozzi, Roberto,Miglio, Gianluca,Bertinaria, Massimo
, p. 10366 - 10382 (2015/02/19)
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
