LY2090314

LY2090314 is potent and selective inhibitor of glycogen synthase kinase 3 (GSK3) with IC₅₀ values of 1.5 and 0.9 nM for human recombinant GSK3α and GSK3β, respectively.¹ It has >10-fold selectivity for GSK3 over a panel of 40 kinases at a concentration of 20 μM. LY2090314 induces time-dependent stabilization of β-catenin total protein and activates Wnt signaling in vitro. It has potent antiproliferative activity in BRAF wild-type/NRAS mutant and BRAF mutant melanoma cell lines (IC₅₀s = 6.0-11.8 nM) but has limited to no activity in non-melanoma cell lines with (IC₅₀s = 430 to >20,000 nM). Knockdown of β-catenin in A375 and M14 melanoma cells induces LY2090314 resistance in vitro, indicating that LY2090314-induced cell death is dependent upon Wnt activation. In vivo, LY2090314 reduces tumor volume in a murine A375 melanoma xenograft model as a single agent and synergizes with decabarzine for a greater antitumor effect. Formulations containing LY2090314 are under clinical investigation for the treatment of advanced solid tumors.²

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1. Atkinson, J.M., Rank, K.B., Zeng, Y., et al. Activating the Wnt/β-catenin pathway for the treatment of melanoma--application of LY2090314, a novel selective inhibitor of glycogen synthase kinase-3. PLoS One 2015, e0125028 (2015).

2. Gray, J.E., Infante, J.R., Brail, L.H., et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest New Drugs 33(6), 1187-1196 (2015).