Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

Autores de CIPF

• 

  Paula Soriano Teruel

  Autor

• 

  Maria Jesus Vicent Docon

  Autor

• 

  Mónica Sancho Medina

  Autor

• 

  Maria Mar Orzáez Calatayud

  Autor

Participantes ajenos a CIPF

• Garcia-Lainez, G
• Marco-Salvador, M
• Pardo, J
• Arias, M
• DeFord, C
• Merfort, I
• Pelegrin, P

Grupos de Investigación

• Laboratorio de Polímeros Terapéuticos

  

  Jefe/a de Grupo

  Maria Jesus Vicent Docon

• Laboratorio de Terapias Dirigidas en Cáncer e Inflamación

  

  Jefe/a de Grupo

  Maria Mar Orzáez Calatayud

Abstract

The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.