LIQ1 is a flavonoid derivative and a potent allosteric inhibitor of pyruvate kinase M2 (PKM2) with an IC50 of 0.39 μM and a Kd of 4.5 μM, targeting the Arg43 in the poly-arginine pocket. It demonstrates efficacy in an LPS-induced mouse endotoxemia model by preventing PKM2 nuclear translocation and inhibiting its interaction with HIF-1α, thus suppressing IL-1β transcription. LIQ1 is applicable in endotoxemia research.

PKM2:0.39 μM

LIQ1 (100 μM; 2 hours) significantly enhances the thermal stability of PKM2 within the temperature range of 40-52 ℃, increasing its melting temperature (T m) by 3.4 ℃. In comparison to wild-type PKM2 (IC 50 = 0.98 μM; K d = 3.2 μM), LIQ1 markedly reduces its inhibitory effect on PKM2 R43A (IC 50 = 4.10 μM; K d = 11.1 μM), indicating that R43 is a crucial residue for mediating allosteric inhibition of PKM2.

Administered at doses of 1, 2, and 5 mg/kg via intraperitoneal injection at 0, 12, 24, and 36 hours post-LPS injection, LIQ1 significantly improved survival rates in mice with LPS-induced endotoxemia, while also mitigating inflammation and organ damage. At a dose of 20 mg/kg, whether administered as a single injection or daily for 14 consecutive days, LIQ1 exhibited negligible acute toxicity and showed no hepatotoxicity or nephrotoxicity in mice, indicating a favorable safety profile.