Repurposing approved drugs on the pathway to novel therapies

Abstract

The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

Towards a cancer mission in Horizon Europe: recommendations

“…Targeting multiple tumour driving pathways by combinations of targeted drugs applied concurrently or in a specific order may increase the efficacy of treatment by circumventing mechanisms of primary or acquired resistance [34]. Expanding molecular pathology by multiomics technologies to identify tumour drivers and conducting high-throughput functional in vitro screens in cells carrying the same lesions might lead to new combination therapies and offer opportunities for drug repurposing [35].…”

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

“…De novo drug discovery, usually performed in the pharmaceutical industry, is an expensive and long process. Drug repurposing approaches have been used across a broad spectrum of diseases [108], where many "repurposed" drugs, such as antibiotics, antivirals, and kinase inhibitors, have had clinical success in treatment areas beyond their originally intended use. In a recent study, certain kinase inhibitors, including an inhibitor of PDK1, were able to function as an adjuvant in colistin-resistant bacteria, potentiating the antimicrobial effect in Gram-negative and Gram-positive bacteria [109].…”

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

“…Epidemiological studies revealed a significant increase in the incidence of autoimmune and inflammatory diseases during the last two decades [1]. Accordingly, the total number of patients taking immunosuppressive drugs has been continuously increasing [2]. Long-term administration of immunosuppressive medications is inevitably associated with increased risk of infection and malignancy due to the sustained suppression of anti-microbial and anti-tumor immunity [3].…”