High-Risk Neuroblastoma Stage 4 (NBS4): Developing A Medicinal Chemistry Multi-Target Drug Approach

Childhood neuroblastoma (NB) is a malignant tumour that is a member of a class of embryonic tumours that have their origins in sympathoadrenal progenitor cells. There are five stages in the clinical NB staging system: 1, 2A, 2B, 3, 4S, and 4. For those diagnosed with stage 4 neuroblastoma (NBS4) the treatment options are limited with a survival rate of between 40 to 50%. Since 1975, more than 15 targets have been identified in the search for a treatment for high-risk NBS4. This article is concerned with the search for a multi-target drug treatment for high-risk NBS4 and focuses on four possible treatment targets that research has identified as having a role in the development of NBS4 and includes the inhibitors Histone Deacetylase (HDAC), Bromodomain (BRD), Hedgehog (HH), and Tropomyosin Kinase (TRK). Computer-aided drug design and molecular modelling have greatly assisted drug discovery in medicinal chemistry. Computational methods such as molecular docking, homology modelling, molecular dynamics, and quantitative structure-activity relationships (QSAR) are frequently used as part of the process for finding new therapeutic drug targets. Using these methods, 8 compounds (inhibitors) were identified as possible inhibitors for all four targets. Results revealed that all four targets BRD, HDAC, HH and TRK share similar amino acid sequencing that ranges from 80-100% offering the possibility of further testing for multi-target drug use. Two additional targets were also tested as part of this work, Retinoic Acid (RA) and c-Src (Csk) which showed similarity across their receptors of 80-100% but lower that 80% for the other four targets. The work for these two targets is the subject of a paper currently in progress.