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Description

A cell-permeable thienopyrrolopyridazinone that exhibits good aqueous solubility (29.6 µ,g/mL or 79.5 µ,M in PBS, pH 7.4) and acts as a potent allosteric PKM2 activator (AC50 = 92 nM, [PKM2] = 0.1 nM) by stabilizing PKM2 tetramer via stoichiometric interaction with FBP-bound PKM2 (2 activator/4 FBP/tetramer) in a similar manner as PKM2 Activator III (Cat. No. 504537). Reprorted to retard human lung carcinoma H1299 proliferation under hypoxia, but not normoxia, condition in cultures (doubling time = 50 and 35 h, respectively, with or without 30 µ,M TEPP-46, 1% O2) in vitro and impair H1299 tumorigenesis in mice (50 mg/kg/12 h p.o.) in vivo with no apparent toxicity., A cell-permeable thienopyrrolopyridazinone that acts as a potent allosteric PKM2 activator (AC50 = 92 nM, [PKM2] = 0.1 nM) via stoichiometric interaction (Two activator molecules per tetramer) with FBP-bound PKM2 tetramer (One FBP per monomer) in a similar manner as PKM2 Activator III (Cat. No. 504537), resulting in highly stabilized PKM2 tetramer resistant to dissociation in the presence of phosphotyrosine-containing peptide/protein or upon PKM2 K305Q mutation. Reported to exhibit good aqueous solubility (29.6 microg/mL or 79.5 microM in PBS, pH 7.4) and retard human lung carcinoma H1299 proliferation under hypoxia, but not normoxia, condition in cultures (doubling time = 50 and 35 h, respectively, with or without 30 microM TEPP-46, 1% O2) in vitro. TEPP-46 is bioavailable in mice via i.p. (Tmax = 0.5 h, Cmax = 10.854 microg/mL, AUCINF = 26.994 hr.microg/mL, 10 mg/kg) or p.o. (Tmax = 0.25 h, Cmax = 10.179 microg/mL, AUCINF = 24.350 hr.microg/mL, 10 mg/kg) administration and shown to impair H1299 tumorigenesis in mice (%tumor development/av. tumor weight = 30%/0.13 mg and 70%/2.6 mg, respectively, with or without 50 mg/kg/12 h oral dosage for 7 wks) in vivo with no apparent toxicity.