One of the leading examples of serendipitous drug repurposing is the story of Pfizer’s little blue pill, Viagra (Figure 1). Viagra was an almost overnight success and is one of the highest grossing drugs in history, yet this sensational pill would have been shelved alongside other failed drugs if not for an unexpected side effect arising during clinical trials. Viagra (or Sildenafil citrate) was originally discovered and tested for the treatment of angina – chest pain experienced when the heart fails to receive enough oxygen – an effect normally associated with coronary heart disease.
The drug works by inhibiting the phosphodiesterase type 5 (PDE5) enzyme which widens blood vessels and supplies heart with additional blood and lowering blood pressure. Viagra’s clinical trials yielded disappointing results, with little efficacy shown in the treatment of angina. Fortunately, volunteers discretely reported incidences of erections when taking Viagra and Pfizer quickly shifted Viagra from treating heart pathology to treating ‘matters of the heart’, providing relief to men suffering from erectile dysfunction. Increased understanding of Viagra’s underlying biology has led Viagra to be repurposed once again and it is now commonly prescribed as a safe treatment for pulmonary arterial hypertension (Figure 2).
Drug repurposing is the process of finding new indications for existing therapeutics and has become an important pipeline for pharmaceutical companies. This approach avoids the huge cost and long delays incurred when developing drugs from the ground up and lowers the financial barrier to entering the commercial market. As such, companies are exploring drugs on the market or salvaging assets that demonstrated poor efficacy and testing them in alternative pathologies. These compounds have already gone through rigorous clinical testing, with safety data from these studies permitted as support for new regulatory approval thereby shortening the transition from bench to bedside. Researchers have used several strategies to find repurposing opportunities, such as costly disease models or broader, but less informative, phenotypic screens.
Cyclica’s proteome-wide screening promotes rapid drug discovery and has direct application in ascertaining a candidate compound’s capabilities for treating other diseases. Ligand Express™ makes it possible to anticipate a compound’s impact on biological systems by generating proteome binding profiles consisting of predicted, ranked drug-protein interactions. Binding profiles include all structurally characterized proteins, leading to the discovery of novel disease associations, and importantly, the scope goes beyond conventional/block-buster diseases and into the realm of rare and orphan diseases. Furthermore, Ligand Express™ generates these unique predictions for approved drugs in a time and cost efficient manner. Lastly, Cyclica’s in silico analysis takes into account an agent’s polypharmacology, which helps prioritize leads to those with the most potential. Repurposing safe compounds has helped rejuvenate drug discovery for both widespread and rare diseases and improve the success rate of new therapeutics. With Cyclica’s technology, and just a hint of serendipity, it is possible to develop much needed therapies faster than ever.