POLYPHARMACOLOGY: CREATING SELECTIVE NON-SELECTIVITY

Drug discovery has contributed greatly to advancing the life sciences and the wellbeing of society in the past century. However, several diseases remain incurable and we are facing an unpredictable productivity crisis. In the last 20 years, while the costs of R&D have steadily increased, there has been a gradual decline in its productivity, as measured by the number of new approved molecular entities. This has been attributed to drug discovery’s gradual move from an entirely human phenotype-based endeavor to the so-called ‘reductionist approach’. This approach attempts to reduce drug action to the level of individual genes, single proteins, and one potential modulating molecule. Thus, the ‘one gene, one target, one drug’ paradigm seeks to generate potent and exquisitely selective ligands that could guard against unwanted side effects.1 However, it is now widely accepted that the majority of diseases that threaten humanity are multifactorial, with substantial environmental and genetic components. For this reason, a selective single-target drug might lack efficacy, while a treatment able to address this complexity will have a greater chance of success.2 To this end, there has been growing recognition that polypharmacology might provide therapeutic benefits where traditional single-target drugs have failed. A combination of drugs, which offers the prospect of additional benefits, is being used to treat several complex diseases such as HIV and hypertension. A more recent interpretation of polypharmacology considers single chemical entities able to simultaneously modulate several molecular targets.3 Although these concepts emerged less than 10 years ago, multitarget kinase inhibitors are already a reality in cancer therapy.4 Their introduction into the market provided the pharmaceutical community with the proof of concept that a ligand with a rationally designed multimodal mechanism of action would not have intrinsically overwhelming toxicity. Other successful examples of multitarget drugs combining high efficacy with reasonable safety are emerging in the fields of neurodegeneration5 and depression. It is highly conceivable that several others will be identified in the near future, bridging the conceptual gap between specific and nonselective drugs.