9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Anti-cancer Drugs
Andrey UgolkovAndrew P Mazar

Abstract

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3β inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

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Citations

Mar 18, 2020·Expert Opinion on Therapeutic Targets·Li Ding, Daniel D Billadeau
May 6, 2020·Cells·Przemysław DudaJames A McCubrey
Aug 26, 2020·Expert Opinion on Therapeutic Patents·Carlos Roca, Nuria E Campillo

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Methods Mentioned

BETA
xenograft
Assay

Software Mentioned

GraphPad Prism

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