Abstract

Irretrievable cardiomyocyte loss after myocardial infarction leads to heart failure, which has evolved into one of the greatest epidemics ever to confront mankind. Discovering a drug to create new heart muscle cells is a central aspiration of regenerative medicine, and is based on the concept that an ideal drug could enhance the adult heart’s natural regenerative capacity, which is underpowered relative to cell death after infarction. To discover bioactive molecules and potential drugs, small molecule libraries have been screened using phenotypic bioassays for cardiogenesis from stem cells and even whole organisms. Although numerous cardiogenic compounds have been described, the overall success of the chemical genetic approach has been constrained by the complexity of the cellular phenotype, the arduous task of deconvoluting cellular targets, coupled with the small portion of the proteome that is interrogated by current chemical libraries. Here we discuss the chemical genetics approach, its successes and limitations, and new strategies of chemical proteomics and functional genomics that promise to unveil the logic of cardiogenesis.

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