Longevity & AgingNew NLRP3 inhibitor blocks inflammation through a different route than MCC950
Chronic inflammation drives many age-related diseases, and the NLRP3 inflammasome is a key trigger. Most NLRP3 drugs in development copy MCC950, which has known limits, including weak activity against some disease-causing NLRP3 mutations. Researchers characterized BAL-0028, an indazole compound found through a DNA-encoded library screen, and its derivative BAL-0598. Both inhibit NLRP3 in human and primate cells at nanomolar potency, with no effect on the AIM2, NLRC4 or NLRP1 inflammasomes at concentrations below 10 μM. They do not block NLRP3's ATPase activity and bind the NACHT domain at a site separate from MCC950's pocket. They barely work on mouse, rat, dog or rabbit NLRP3, but BAL-0598 worked in humanized NLRP3 mice. Both outperformed MCC950 against select hyperactive mutations.
