Longevity & AgingCancer Drug GSK461364 Shuts Down NLRP3 Inflammasome Inflammation in Mice
Overactive NLRP3 inflammasomes drive many inflammatory diseases, yet most NLRP3-targeting drugs have stalled in clinical development. Researchers screened 429 kinase inhibitors in mouse macrophages and found GSK461364, a PLK1 inhibitor that was already tested in cancer trials, strongly blocked NLRP3-dependent IL-1β release. It did not affect AIM2 or NLRC4 inflammasomes. In mice, it reduced inflammation in LPS-induced endotoxemia and DSS-induced colitis without visible toxicity over 9 days. Mechanistically, PLK1 appears to phosphorylate NEK7, likely at Ser221 and Ser260, which strengthens NEK7-NLRP3 binding needed for inflammasome assembly. Blocking PLK1 reduces this phosphorylation and inflammasome activation. The work is preclinical, but it suggests repurposing PLK1 inhibitors for NLRP3-driven inflammation.
