ZLN024 (hydrochloride)

C13H14BrClN2OS

DMSO : >= 46 mg/mL (127.18 mM)

Epigenetics; PI3K/Akt/mTOR

ZLN024 hydrochloride is an AMPK allosteric activator. ZLN024 directly activates recombinant AMPK alpha1beta1gamma1, AMPK alpha2beta1gamma1, AMPK alpha1beta2gamma1 and AMPK alpha2beta2gamma1 heterotrimer with EC₅₀s of 0.42 uM, 0.95 uM, 1.1 uM and 0.13 uM, respectively. IC50 & Target: EC50: 0.42 uM, 0.95 uM, 1.1 uM and 0.13 uM (AMPK alpha1beta1gamma1, alpha2beta1gamma1, alpha1beta2gamma1 and alpha2beta2gamma1 heterotrimer)^[1] In Vitro: ZLN024 allosterically stimulates active AMPK heterotrimers and the inactive alpha1 subunit truncations alpha1 (1-394) and alpha1 (1-335) but not alpha1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Calpha. ZLN024 activates AMPK in L6 myotubes and stimulates glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. Using the established scintillation proximity assay (SPA) assay, random screening against the AMPK alpha1beta1gamma1 heterotrimer is performed and a new AMPK activator, ZLN024 is found. ZLN024 directly activates recombinant AMPK alpha1beta1gamma1 and its homologue alpha2beta1gamma1 in a concentration-dependent manner. ZLN024 increases the activity of alpha1beta1gamma1 by 1.5-fold and has an EC₅₀ of 0.42 uM, and it increases the activity of alpha2beta1gamma1 by 1.7-fold with an EC₅₀ of 0.95 uM. ZLN024 also directly activates recombinant AMPK alpha1beta2gamma1, by 1.7-fold with an EC₅₀ of 1.1 uM; and AMPK alpha2beta2gamma1, by 1.6-fold with an EC₅₀ of 0.13 uM^[1]. In Vivo: C57BKS db/db mice are administered a 15 mg/kg/day dose of ZLN024 by daily gavage for 5 weeks; 250 mg/kg/day Metformin (Met) is used as a positive control. During the treatment period, there is no significant alteration in food intake and body weight compared with the vehicle group. After 4 weeks of treatment, ZLN024 improves glucose tolerance. ZLN024 reduces the fasting blood glucose by 15%. Liver tissue weight, triacylglycerol and the total cholesterol content are decreased^[1].