Therapeutic Targeting of Repurposed Anticancer Drugs in Alzheimer's Disease: Using the Multiomics Approach

Abstract

Aim/Hypothesis: The complexity and heterogeneity of multiple pathological features make Alzheimer's disease (AD) a major culprit to global health. Drug repurposing is an inexpensive and reliable approach to redirect the existing drugs for new indications. The current study aims to study the possibility of repurposing approved anticancer drugs for AD treatment. We proposed an in silico pipeline based on "omics"data mining that combines genomics, transcriptomics, and metabolomics studies. We aimed to validate the neuroprotective properties of repurposed drugs and to identify the possible mechanism of action of the proposed drugs in AD. Results: We generated a list of AD-related genes and then searched DrugBank database and Therapeutic Target Database to find anticancer drugs related to potential AD targets. Specifically, we researched the available approved anticancer drugs and excluded the information of investigational and experimental drugs. We developed a computational pipeline to prioritize the anticancer drugs having a close association with AD targets. From data mining, we generated a list of 2914 AD-related genes and obtained 49 potential druggable targets by functional enrichment analysis. The protein-protein interaction (PPI) studies for these genes revealed 641 interactions. We found that 15 AD risk/direct PPI genes were associated with 30 approved oncology drugs. The computational validation of candidate drug-target interactions, structural and functional analysis, investigation of related molecular mechanisms, and literature-based analysis resulted in four repurposing candidates, of which three drugs were epidermal growth factor receptor (EGFR) inhibitors. Conclusion: Our computational drug repurposing approach proposed EGFR inhibitors as potential repurposing drugs for AD. Consequently, our proposed framework could be used for drug repurposing for different indications in an economical and efficient way.