Screening NLRP3 drug candidates in clinical development: lessons from existing and emerging technologies.

Decades of evidence positioned IL-1β as a master regulatory cytokine in acute and chronic inflammatory diseases. Approved biologics aimed at inhibiting IL-1 signaling have shown efficacy but variable safety. More recently, targeting NLRP3 activation, an upstream mediator of IL-1β, has garnered the most attention. Aberrant NLRP3 activation has been demonstrated to participate in the progression of several pathological conditions from neurogenerative diseases to cardio-metabolic syndromes and cancer. Pharmacological and genetic strategies aimed to limit NLRP3 function have proven effective in many preclinical models of diseases. These evidences have lead to a significant effort in the generation and clinical testing of small orally active molecules that can target NLRP3. In this report, we discuss different properties of these molecules with translational potential and describe the technologies currently available to screen NLRP3 targeting molecules highlighting advantages and limitations of each method.

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Copyright © 2024 Tengesdal, Banks, Dinarello and Marchetti.

Déclaration de conflit d'intérêts

IT serves as consultant for Olatec and receives compensation. CD serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation, and has equity in Olatec. CM serves as Director for Olatec’s Innovative Science Program and has equity in Olatec. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.