Graphical 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.

Senescence is a persistent state of cell cycle arrest. Induction of senescence has been explored as a barrier against tumor progression and is used as a therapeutic option. Despite the advantages of the introduction of senescence‐inducing compounds in the clinic, recent studies show that their side‐effects can be partially masking their antitumor potential. This is due to the deleterious effects that accumulation of senescent cells in tissues and organs causes on tissue microenvironment that confer tumor‐promoting properties. In this study, it is demonstrated that the presence of senescent endothelium favors cancer cell migration and show that palbociclib systemic treatment induces senescence in veins in an orthotopic triple‐negative breast cancer mouse model. Moreover, it is found that following palbociclib‐induced senogenesis, the elimination of senescent cells using the nanoencapsulated senolytic navitoclax (NP(nav)‐Gal) produces the selective elimination of endothelial senescent cells and induces a marked recovery of endothelial tissue functionality. Finally, the treatment with NP(nav)‐Gal produces a significant decrease of senescence in veins which is consistent with the decrease in metastasic burden observed. These results evidence the potential of reducing vascular senescence using senolytic therapies as a strategy to limit the metastatic dissemination of tumors cells in breast cancer patients subjected to chemotherapeutic treatments.

Inflammasomes are multiprotein complexes that represent critical elements of the inflammatory response. The dysregulation of the best-characterized complex, the NLRP3 inflammasome, has been linked to the pathogenesis of diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer’s disease, and cancer. While there exist molecular inhibitors specific for the various components of inflammasome complexes, no currently reported inhibitors specifically target NLRP3PYD homo-oligomerization. In the present study, we describe the identification of QM380 and QM381 as NLRP3PYD homo-oligomerization inhibitors after screening small molecules from the MyriaScreen library using a split-luciferase complementation assay. Our results demonstrate that these NLRP3PYD inhibitors interfere with ASC speck formation, inhibit pro-inflammatory cytokine IL1-β release, and decrease pyroptotic cell death. We employed spectroscopic techniques and computational docking analyses with QM380 and QM381 and the PYD domain to confirm the experimental results and predict possible mechanisms underlying the inhibition of NLRP3PYD homo-interactions.

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