PRECLINICAL REPORTS9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastomaUgolkov, Andrey V.a,d; Bondarenko, Gennadiy I.d; Dubrovskyi, Oleksiid; Berbegall, Ana P.e,f; Navarro, Samuele,f; Noguera, Rosae,f; O’Halloran, Thomas V.c,d; Hendrix, Mary J.c; Giles, Francis J.a,c; Mazar, Andrew P.b,c,dAuthor Information aDepartment of Medicine, Developmental Therapeutic Program, Division of Hematology/Oncology bDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University cRobert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago dChemistry of Life Processes Institute, Northwestern University, Evanston, Illinois eDepartment of Pathology, Medical School, University of Valencia-INCLIVA, Valencia fCancer CIBER (CIBERONC), Madrid, Spain Correspondence to Andrew P. Mazar, PhD, Monopar Therapeutics, Inc. 5 Revere Drive, Suite 200, Northbrook, IL 60062, USA Tel: +1 847 388 0349 x403; e-mail: [email protected] Received March 23, 2018 Accepted May 1, 2018 Anti-Cancer Drugs: September 2018 - Volume 29 - Issue 8 - p 717-724 doi: 10.1097/CAD.0000000000000652 Buy Metrics 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. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.