ZG-2291 is a highly potent, selective and in vivo active factor inhibiting HIF (FIH) inhibitor with Ki of 65.3 nM, 39-fold selective over PHD2.
ZG-2291 induces conformational flipping of Tyr102.
ZG-2291 has a high affinity to FIH with a Kd of 99.7 nM in ITC assays, with much weaker binding to PHD2 with a Kd of 5.58 uM.
ZG-2291 is highly selective for FIH over all the other 2OG-dependent JmjC KDMs, including KDM3A,KDM4A, KDM4C, and KDM4D.
ZG-2291 regulates FIH-dependent HIF target gene expressionin cells.
ZG-2291 promotes thermogenesis and improves lipid accumulation in 3T3-L1-derived adipocytes, decrease cellular TG levels and reduce lipid accumulation, soimproving cellular lipid homeostasis.
ZG-2291 (10 mg/kg) protects against obesity, ameliorates symptoms of obesity and associated metabolic dysfunction in ob/ob mice.
ZG-2291 strongly upregulates the uncoupling protein 1 (UCP1) inwhite adipose tissue, so triggering thermogenesis and ameliorating obesity.