Drug Repurposing in Chemoresistance

Drug repurposing is a methodology for identifying new uses for regulatory approved or investigational drugs outside the scope of the original therapeutic indication. Chemoresistance in infectious diseases and cancer is an important area for repurposing because of the need to add to the therapeutic armamentarium, the potential to reduce the time taken from discovery to the clinic, the potential to reduce the cost of new drug development, if successful to play a potential role in reducing in part the cost burden in health provision and finally the potential to use drugs in new settings where their existing pharmacological properties are well established. In addition, despite the genomic revolution, therapeutic advances have often not translated into clinical benefit (1, 2). Repurposing of existing therapeutics draws on two principles. Firstly, most clinical disease is multifactorial, and secondly pleiotropy, is a characteristic that can occur with existing approved therapeutics. As such, the off-target potential of existing drugs in combination the multifactorial nature of complex diseases was the stimulus for our research for over a decade.

Three examples briefly illustrate our approach to drug repurposing.

1. A recognition that butyrate (a product of resistant starch fermentation in the colon (3) with an interaction with p-53 and HDAC) shares structural properties with the drug valproate. Importantly valproate is well established as an anti-convulsant and as such crosses the blood brain barrier and as we highlighted the aliphatic acids such as valproate and butyrate have also been shown to possess HDAC inhibitory properties (4).This led to our studies on effect of valproic acid in combination with irradiation and temozolomide treatment on primary human glioblastoma cells (4).

2. The dysregulation of protein kinases is frequently a characteristic of cancer. Together with collaborators we employed in silico and in vitro approaches, to seek potential kinase-targeted drug candidates from a portfolio of non-cancer therapeutics (5). The use of ligand-based 3D screening and cell biological analysis revealed that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor (5).

3. In the early stages of the COVID-19 pandemic the global interest in repurposing drugs to achieve prevention or to treat the symptoms associated with the pathophysiology of this viral infection. We developed a pharmacological framework for harmonizing the principles of treating the host, drug repurposing and integration with the damage response framework in COVID-19 disease (6).

We have recognised the importance multi-disciplinary non-siloed scientific teams that combine the experimental power and scale that different disciplines bring to drug repurposing. In this fashion drug repurposing puts substantial logic into revealing drug pleiotropy that historically was often revealed by serendipity.