High-risk neuroblastoma stage 4 (NBS4): multi-target inhibitors for c-Src kinases (Csk) and retinoic acid (RA) signalling pathways

Abstract

Aim: This paper investigates two possible treatment targets for neuroblastoma (NB) stage 4 (NBS4), c-Src kinase (Csk) and retinoic acid (RA) signalling pathways as potential candidates for a multi-target drug. Research has demonstrated that many cancer cells overexpress and/or hyperactivate c-Src, a tyrosine that is a member of the Src-family kinases. In the case of NBS4, there are indications that successful inhibition of c-Src could inhibit disease progression. Research into the altered signalling of RA, which preserves the differentiated state of adult neurons, neural stem cells, and NB cells (SH-SY5Y), is also investigated as a potential multi-target drug.

Methods: Using computer-aided technology, including OpenEye Scientific suite, Molegro Virtual docking, Samson suite, and Discovery Studio Visualiser, the results revealed that the receptors for both targets, Csk and RA, share similar amino acid sequencing that ranges from 80–100%, offering the possibility of further testing for multi-target drug use. Work was done to explore possible synthesis routes for each of the four compounds using the retrosynthesis program Spaya. Predictive toxicology was done using the Toxicity Estimation Software Tool (T.E.S.T.).

Results: Four compounds (inhibitors) targeting the Csk tyrosine kinase and RA pathways were identified as potential inhibitors.

Conclusions: Currently, no effective therapeutic agents for NBS4 exist. Immunotherapy which has proven effective in treating various cancers, is currently used to treat NBS4 and has a 40% to 50% survival rate. This paper investigates two possible treatment targets for NBS4, Csk and RA signalling pathways as possible candidates for a multi-target drug. Four potential inhibitors have been identified.

Keywords

Neuroblastoma stage 4 (NBS4) / receptors / multi-target drugs / docking / cross-docking / binding interaction

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