GI-Y2 

GI-Y2 is an orally active, selective Gasdermin D (GSDMD) inhibitor (K_d = 36.0 μM) with anti-pyroptosis activity. GI-Y2 targets GSDMD, impairs membrane anchoring of GSDMD-NT, and blocks GSDMD‑dependent lipid binding and pore formation. GI-Y2 suppresses GSDMD‑dependent pyroptosis and inflammation, mitigates atherosclerosis and cardiac injury, boosts cell survival, and reduces IL‑1β/IL‑18 secretion. GI-Y2 can be used for the research of atherosclerosis and septic myocardial injury^[1][2].

GI-Y2 suppresses LPS+Nigericin (HY-127019)-induced pyroptosis in PMA-differentiated THP-1 cells with an IC₅₀ of 35.40 μM by binding to the Arg10 residue of GSDMD via hydrogen bonding to reduce GSDMD-NT membrane localization^[1][2].
GI-Y2 (2.5-40 μM) directly binds to purified GST-GSDMD protein with a K_d value of 36.0 μM^[1].
GI-Y2 (10 μM; 1 h) directly interacts with Flag-GSDMD expressed in HEK/293T cells, as evidenced by reduced pronase-mediated degradation of GSDMD at 10 μM^[1].
GI-Y2 inhibits GSDMD-mediated pyroptosis in human AC16, HEK-293T, and HepG2 cell lines^[1].
GI-Y2 (10 μM; 1 h) reduces GSDMD-N membrane binding and pyroptotic LDH release in HEK/293T cells expressing wild-type Flag-GSDMD, but not in cells expressing the GSDMD^R10A mutant, confirming Arg10 as the critical binding site^[1].
GI-Y2 (10-20 μM; 1 h) dose-dependently inhibits ox-LDL-induced pyroptosis in ApoE^−/− mouse primary peritoneal macrophages, reducing lipid uptake, inflammatory cytokine production, and GSDMD-N activation^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

GI-Y2 (20 mg/kg; i.g.; twice) improves survival and reduces pyroptosis-related cytokine levels in a mouse model of LPS-induced sepsis^[1].
GI-Y2 (10-20 mg/kg; i.g.; every 2 days; 6 weeks) dose-dependently reduces atherosclerotic plaque formation, pyroptotic inflammation, and immune cell infiltration in ApoE^−/− mice fed a high-fat diet^[1].
GI-Y2 (20 mg/kg; i.g.; every 2 days; 6 weeks) does not provide additional protection against atherosclerosis in Gsdmd-deficient ApoE^−/− mice, confirming its effects are mediated via targeting GSDMD^[1].
GI-Y2 (0.03 mg/kg; i.v.; every 3 days; 4 weeks) reduces atherosclerotic plaque formation in ApoE^−/− mice, with enhanced efficacy when delivered via macrophage membrane-coated nanoparticles^[1].
GI-Y2 improves survival and decreases pro-inflammatory cytokine levels in septic mice. GI-Y2 attenuates atherosclerotic lesions and septic myocardial injury by targeting GSDMD-mediated pyroptosis, and its therapeutic efficacy is significantly enhanced by macrophage membrane-coated nanoparticle delivery^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

386.38

C₁₈H₁₄N₂O₆S

1008710-58-4

OC(C1=CC=C(CN2C(SC(NC3=CC=C(C(O)=O)C=C3)C2=O)=O)C=C1)=O

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Fan X, et al. The novel GSDMD inhibitor GI-Y2 exerts antipyroptotic effects to reduce atherosclerosis. Clin Transl Med. 2025;15(3):e70263.  [Content Brief]

  [2]. Shua Y, et al. Progress in small-molecule inhibitors of gasdermin D. Eur J Med Chem. 2025;300:118171.