Discovery and characterization of PGC-01: An effective GSDMD-targeting PROTAC.

Abstract

As the key executioner protein of pyroptosis, GSDMD represents a promising yet underexplored therapeutic target for inflammatory diseases. In this study, we explored a PROTAC-based degradation approach targeting GSDMD for the treatment of pyroptosis-driven inflammatory conditions. Through screening of our in-house compound library, we identified a high-affinity GSDMD binder, PGC (KD = 9.42 nM). Through rational design of linkers and systematic optimization of the E3 ligase attachment site, we constructed a series of PROTACs and identified PGC-01 as a CRBN-recruiting and effective GSDMD degrader (DC50 = 3.32 μM, Dmax = 85%). Functionally, PGC-01 concentration-dependently suppressed nigericin-induced macrophage pore formation, cell death, and IL-1β release. In vivo, rectal administration of PGC-01 dose-dependently alleviated clinical symptoms and pathological damage in a DSS-induced murine colitis model. Collectively, this study provides critical proof-of-concept that targeted degradation of GSDMD is a viable therapeutic strategy and positions PGC-01 as a promising lead compound for the treatment of GSDMD-driven inflammatory diseases.