Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

TLDR

The NLRP3 inflammasome is implicated in many human diseases, yet no selective direct inhibitors exist, leaving its therapeutic targetability uncertain. CY‑09 binds the ATP‑binding motif of the NLRP3 NACHT domain, inhibiting its ATPase activity and thereby preventing inflammasome assembly and activation. CY‑09 selectively blocks NLRP3 activation, providing therapeutic benefit in mouse models of CAPS and type 2 diabetes and acting on human monocytes and gout synovial cells, demonstrating that NLRP3 can be targeted in vivo.

Abstract

The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.