Recycling side-effects into clinical markers for drug repositioning

For almost a century, drug discovery was driven by the quest for magic bullets, which act by targeting one critical step in a disease process and elicit a cure with few other consequences. However, this concept is far from biological reality, and even the most successful rationally designed drugs (such as Gleevec？) show a quite promiscuous binding behavior, which has opened novel therapeutic possibilities [1]. Today, the emerging picture is that drugs rarely bind specifically to a single target, and this challenges the concept of a magic bullet. Indeed, recent analyses of drug and drug-target networks show a rich pattern of interactions among drugs and their targets, where drugs acting on a single target seem to be the exception. Likewise, many proteins are targeted by several drugs with quite distinct chemical structures [2].Drug-repositioning strategies seek to exploit the notion of polypharmacology [3], together with the high connectivity among apparently unrelated cellular processes, to identify new therapeutic uses for already approved drugs. The main advantage of this approach is that, since it starts from approved compounds with well-characterized pharmacology and safety profiles, it should drastically reduce the risk of attrition in clinical phases. There are several successful examples of drug repositioning (for example, thalidomide to treat leprosy or finasteride for the prevention of baldness), although they were all found by serendipity and are not the result of well-thought strategies.More recently, and following the observation that most novel entities are found by phenotypic profiling techniques [4], systematic initiatives to find new indications for old drugs have flourished. These approaches rely mostly on genome-wide transcriptional expression data from cultured human cells treated with small molecules, and pattern-matching algorithms to discover functional connections between drugs, genes and diseases through concerted gene-expression changes [5].