Reconsidering phenotypic heart failure drug discovery

Abstract

With a few notable exceptions, heart failure (HF) drug development has faced substantial attrition while translating preclinical discoveries into clinical efficacy. The high attrition has prompted a reconsideration of the target selection process of drug discovery. The industry standard of selecting drug targets based upon guidance from the published scientific literature has proven of limited reliability and has prompted a resurgent interest in phenotypic drug discovery (PDD). PDD, which has been reported to have an improved drug development success rate, offers an experimental route to drug target selection. In PDD, the drug targets, the disease relevant biological mechanisms and the drugs themselves are all selected by the phenotypic screen. For HF, with highly reproducible pathologic cellular phenotypes and recently developed human cell lines, the infrastructure necessary for PDD programs is well established. Despite an urgent necessity to improve drug discovery strategies, the challenges posed by PDD to both the capabilities and culture of the pharmaceutical industry are formidable.