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.

Keywords: antibiotic combination therapy; anticancer; antiviral therapies; immunosuppressive; interferons; novel uses for approved drugs; pathogen resistance pathways; tetracycline derivatives; thalidomide derivatives; toxin inhibitors; tumor necrosis factor.

Figure 1

Rose Bengal dye (red food dye no. 105), now in clinical trials as an anticancer agent, has low solubility and serum half‐life

Figure 2

Favipiravir (T‐705, avigan), a pyrazine carboxamide derivative, inhibits many different viral polymerases at high concentrations