Uses
LY 2090314 is a novel glycogen synthase kinase-3α inhibitor for the treatment of acute myeloid leukemia.
Definition
ChEBI: LY-2090314 is a member of the class of diazepinoindoles that is 1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indole substituted by piperidin-1-ylcarbonyl, 4-(imidazo[1,2-a]pyridin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl and fluoro groups at position 2, 7 and 9, respectively. It is a potent ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK-3) with IC50 values of 1.5 nM and 0.9 nM for GSK-3alpha and GSK-3beta. The drug is in clinical development for the treatment of advanced/metastatic cancer. It has a role as an apoptosis inducer, an antineoplastic agent, a Wnt signalling activator and an EC 2.7.11.26 (tau-protein kinase) inhibitor. It is an imidazopyridine, a diazepinoindole, a member of monofluorobenzenes, a piperidinecarboxamide, a member of ureas and a member of maleimides.
Biological Activity
ly2090314 (ly) is a potent inhibitor of glycogen synthase kinase-3 (gsk-3) which plays an important role in various pathways, such as protein synthesis initiation, cell proliferation/differentiation, and apoptosis.
Biochem/physiol Actions
LY2090314 is a potent and selective ATP-competitive inhibitor of Glycogen synthase kinase-3 (GSK-3) currently in clinical trials for cancer therapy. LY2090314 has IC50 values of 1.5 nM and 0.9 nM for GSK-3α and GSK-3β, respectively.
in vitro
ly2090314 selectively inhibits the activity of gsk-3 by inhibiting atp binding. ly2090314 was reported to be able to stabilize β-catenin. as monotherapy, ly2090314 aslso showed limited efficacy. in solid tumor cancer cell lines, ly3090314 was found to enhance the efficacy of cisplatin and carboplatin [1].
in vivo
even in mdr1a-, bcrp-, and mrp2-knockout rats, the metabolites of ly2090314 did not appear in systemic circulation, and the urinary excretion was not found to be enhanced, since the hypothesized impaired biliary excretion of metabolites in the absence of these canalicular transporters was not observed. dog metabolite disposition was similar, with the exception of ly2090314 glucuronide. moreover, ly2090314 enhances the efficacy of cisplatin and carboplatin in solid tumor cancer xenografts [1]
IC 50
1.5 nm (gsk-3α); 0.9 nm (gsk-3β)
References
[1] brail lh, et al. j clin oncol, 2011, 29, abstr 3030.
