ENDO12

ENDO12 is an inhibitor of the Munc13-4-STX7 protein complex, with a K d value of 2.7 µM for STX7. ENDO12 blocks the interaction of Munc13-4-STX7. ENDO12 inhibits endolysosomal flux, endolysosomal cargo degradation, the extracellular signal-regulated kinase signaling pathway in neutrophils, the IFN regulatory factor signaling pathway in plasmacytoid dendritic cells, and the responses of primary dendritic cells to TLR3, TLR7, and TLR9. ENDO12 alleviates CpG-induced systemic inflammation by reducing the levels of myeloperoxidase, IL-6 and IFNγ. ENDO12 does not interfere with the host's antiviral response to lymphocytic choriomeningitis virus infection.\nENDO12 can be used in studies related to systemic inflammation ^[1].

In Vivo, ENDO12 (30 mg/kg; i.p.; single dose; 1 hour before CpG challenge) reduces CpG-induced systemic inflammation in mice, lowering plasma IL-6, IFNγ, and MPO levels^[1]. ENDO12 (15 mg/kg; i.p.; single dose; 1 hour before LCMV infection) does not impair the host antiviral response to LCMV infection in mice, with only minimal reduction in MIP1β and MIP2 levels^[1].

In Vitro, ENDO12 (31.25 nM-3 μM) binds to recombinant STX7 with a Kd value of 2.7 µM, showing higher affinity than ENDO3^[1]. ENDO12 potently inhibits CpG-induced TLR9 activation in HEK-Blue hTLR9 cells, with an IC₅₀ of 1 × 10-7 M^[1]. ENDO12 (10 µM; 1 h) reduces the colocalization levels of STX7 with Munc13-4, TLR7 with LAMP1, and TLR9 with LAMP1 in RAW 264.7 mouse macrophages, thereby inhibiting endosome maturation and TLR trafficking^[1].

References:
[1]. Johnson JL, et al. Munc13-4-STX7 inhibitors impair endosomal TLR activation and systemic inflammation. Nat Chem Biol. Published online April 6, 2026.