Promiscuously bioactive compounds are prevalent in widely used commercial drug repurposing libraries

The discovery of new therapeutics typically begins with screening compound collections against specific disease targets to identify bioactive small molecules. However, subsequent optimization is both time-consuming and costly, leading researchers to search for desired bioactivity in already-approved drugs with the hope of accelerating clinical development - a strategy often termed drug repurposing. While this strategy may seem beneficial, it carries significant risks, in particular with respect to lack of intellectual property control required to navigate regulatory pathways to the clinic. In this study, we have identified the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds. Researchers lacking adequate medicinal chemistry expertise may overlook the spurious behaviors linked to certain molecular scaffolds, which can result in the advancement of misleading compounds into clinical trials. This misstep not only wastes scientific and financial resources but also could pose serious risks to patient safety by potentially enrolling them in ineffective trials. We call upon the biomedical community to implement rigorous validation processes for screening hits and to systematically exclude problematic compounds from drug repurposing libraries, thereby increasing the translational rate of future drug repurposing initiatives.