Multiple approaches to repurposing drugs for neuroblastoma. (1st November 2022)

• Record Type: Journal Article
• Authors: Rank, Laura; Puhl, Ana C.; Havener, Tammy M.; Anderson, Edward; Foil, Daniel H.; Zorn, Kimberley M.; Monakhova, Natalia; Riabova, Olga; Hickey, Anthony J.; Makarov, Vadim; Ekins, Sean
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: Drug Discovery -- Machine learning -- Neuroblastoma -- Pyronaridine -- Repurposing; CNR2 Cannabinoid Receptor 2 -- MAPK8 Mitogen-Activated Protein Kinase 8 -- NB Neuroblastoma -- TKIs tyrosine kinase inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117043
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Neuroblastoma (NB) is the second leading extracranial solid tumor of early childhood with about two-thirds of cases presenting before the age of 5, and accounts for roughly 15 percent of all pediatric cancer fatalities in the United States. Treatments against NB are lacking, resulting in a low survival rate in high-risk patients. A repurposing approach using already approved or clinical stage compounds can be used for diseases for which the patient population is small, and the commercial market limited. We have used Bayesian machine learning, in vitro cell assays, and combination analysis to identify molecules with potential use for NB. We demonstrated that pyronaridine (SH-SY5Y IC50 1.70 µM, SK- N -AS IC50 3.45 µM), BAY 11–7082 (SH-SY5Y IC50 0.85 µM, SK- N -AS IC50 1.23 µM), niclosamide (SH-SY5Y IC50 0.87 µM, SK- N -AS IC50 2.33 µM) and fingolimod (SH-SY5Y IC50 4.71 µM, SK- N -AS IC50 6.11 µM) showed cytotoxicity against NB. As several of the molecules are approved drugs in the US or elsewhere, they may be repurposed more readily for NB treatment. Pyronaridine was also tested in combinations in SH-SY5Y cells and demonstrated an antagonistic effect with either etoposide or crizotinib. Whereas when crizotinib and etoposide were combined with each other they had a synergistic effect in these cells. We have also described several analogs of pyronaridine to explore the structure–activity relationship against cell lines. We describe multiple molecules demonstrating cytotoxicity against NB and the further evaluation of these molecules and combinations using other NB cells lines and in vivo models will be important in the future to assess translational potential.