Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Mattia Cocco; Carolina Pellegrini; Helios Martínez Banaclocha; Marta Giorgis; Elisabetta Marini; Annalisa Costale; Gianluca Miglio; Matteo  Fornai; Luca Antonioli; Gloria Lopez-Castejon; Ana Tapia-Abellan; Diego Angosto; Iva Hafner-Bratkovi; Luca Regazzoni; Corrado Blandizzi; Pablo Pelegrin; Massimo Bertinaria

doi:10.1021/acs.jmedchem.6b01624

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Mattia Cocco, Carolina Pellegrini, Helios Martínez Banaclocha, Marta Giorgis, Elisabetta Marini, Annalisa Costale, Gianluca Miglio, Matteo Fornai, Luca Antonioli, Gloria Lopez-Castejon, Ana Tapia-Abellan, Diego Angosto, Iva Hafner-Bratkovi, Luca Regazzoni, Corrado Blandizzi , Pablo Pelegrin, Massimo Bertinaria

Division of Immunology, Immunity to Infection and Respiratory Medicine

Universita di Pisa

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Abstract

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of Inflammatory
Bowel Disease (IBD). In this work, we report the design, the synthesis, and the 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 non-toxic, 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 DNBSinduced
colitis in rats after oral administration

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	9
Early online date	14 Apr 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01624
Publication status	Published - 2017

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Cocco, M., Pellegrini, C., Martínez Banaclocha, H., Giorgis, M., Marini, E., Costale, A., Miglio, G., Fornai, M., Antonioli, L., Lopez-Castejon, G., Tapia-Abellan, A., Angosto, D., Hafner-Bratkovi, I., Regazzoni, L., Blandizzi , C., Pelegrin, P., & Bertinaria, M. (2017). Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease. Journal of Medicinal Chemistry, 60(9). https://doi.org/10.1021/acs.jmedchem.6b01624

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title = "Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease",

abstract = "Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of InflammatoryBowel Disease (IBD). In this work, we report the design, the synthesis, and the biological screening of a series of acrylatederivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptoticproperties allowed the selection of 11 (INF39), a non-toxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β releasefrom macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interferewith NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of DNBSinducedcolitis in rats after oral administration",

author = "Mattia Cocco and Carolina Pellegrini and {Mart{\'i}nez Banaclocha}, Helios and Marta Giorgis and Elisabetta Marini and Annalisa Costale and Gianluca Miglio and Matteo Fornai and Luca Antonioli and Gloria Lopez-Castejon and Ana Tapia-Abellan and Diego Angosto and Iva Hafner-Bratkovi and Luca Regazzoni and Corrado Blandizzi and Pablo Pelegrin and Massimo Bertinaria",

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doi = "10.1021/acs.jmedchem.6b01624",

language = "English",

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Cocco, M, Pellegrini, C, Martínez Banaclocha, H, Giorgis, M, Marini, E, Costale, A, Miglio, G, Fornai, M, Antonioli, L, Lopez-Castejon, G, Tapia-Abellan, A, Angosto, D, Hafner-Bratkovi, I, Regazzoni, L, Blandizzi , C, Pelegrin, P & Bertinaria, M 2017, 'Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease', Journal of Medicinal Chemistry, vol. 60, no. 9. https://doi.org/10.1021/acs.jmedchem.6b01624

TY - JOUR

T1 - Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

AU - Cocco, Mattia

AU - Pellegrini, Carolina

AU - Martínez Banaclocha, Helios

AU - Giorgis, Marta

AU - Marini, Elisabetta

AU - Costale, Annalisa

AU - Miglio, Gianluca

AU - Fornai, Matteo

AU - Antonioli, Luca

AU - Lopez-Castejon, Gloria

AU - Tapia-Abellan, Ana

AU - Angosto, Diego

AU - Hafner-Bratkovi, Iva

AU - Regazzoni, Luca

AU - Blandizzi , Corrado

AU - Pelegrin, Pablo

AU - Bertinaria, Massimo

PY - 2017

Y1 - 2017

N2 - Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of InflammatoryBowel Disease (IBD). In this work, we report the design, the synthesis, and the biological screening of a series of acrylatederivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptoticproperties allowed the selection of 11 (INF39), a non-toxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β releasefrom macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interferewith NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of DNBSinducedcolitis in rats after oral administration

AB - Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of InflammatoryBowel Disease (IBD). In this work, we report the design, the synthesis, and the biological screening of a series of acrylatederivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptoticproperties allowed the selection of 11 (INF39), a non-toxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β releasefrom macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interferewith NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of DNBSinducedcolitis in rats after oral administration

UR - http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b01624

U2 - 10.1021/acs.jmedchem.6b01624

DO - 10.1021/acs.jmedchem.6b01624

M3 - Article

SN - 0022-2623

VL - 60

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Abstract

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