Pyruvate kinase M2 (PKM2) interacts with phosphotyrosine-containing proteins to regulate glucose metabolism in cells. DASA-58 is a potent activator of recombinant PKM2 with an AC90 value of 680 nM and an AC50 value of 38 nM. In A549-PKM2/kd cell lysates, treatment with 40 μM DASA-58 for 3 hours caused 248% increase of pyruvate kinase activity. Incubation of A549 cells with 0 – 100 μM DASA-58 dose-dependently activated PKM2 with an EC50 value of 19.6 μM. Also in A549 cells, pretreatment with 1 μM DASA-58 prevented pervanadate-induced PKM2 activity inhibition. DASA-58 at 50 μM decreased lactate production in H1299 cells compared to DMSO-treated group. In H1299 cells incubated with [6-14C]-glucose, DASA-58 at 30 μM led to a significant reduction of glucose-derived carbon incorporation into lipids. A549 cells treated with 100 μM DASA-58 showed diminished incorporation of glucose carbons into acetyl-CoA and decreased de novo lipogenesis[3]. Injection of SCID mice with DASA-58-treated PC3 cells (40 μM, 48h incubation) significantly downregulated CAFs-induced lung metastases formation[4].
作用机制
DASA-58 increases PKM2 activity by an allosteric mechanism similar to fructose-1,6-bisphosphate, a glycolytic metabolite fructose that binds to PKM2, inducing a conformational conversion of the enzyme into its most active form[3].
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