Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury

Visual Abstract
Highlights • New CMs in adult mammalians are generated at a low rate, and Hippo–YAP signaling plays crucial roles in the postnatal cardiac regeneration. • After chemical screenings to identify compounds that activate YAP–TEADs activities and CM proliferation in vitro, the authors synthesized a novel multifaceted fluorinated compound TT-10 (C11H10FN3OS2) from a biologically hit compound. • TT-10 induces proliferation of cultured CMs via nuclear translocation of YAP and activation of Wnt/β-catenin signaling, and also activates NRF2-mediated antioxidant and antiapoptotic effects. • The intraperitoneal injection of TT-10 ameliorates cardiac remodeling after MI in mice, which is partially mediated by CM proliferation and by direct antioxidant and antiapoptotic effects in vivo. • Stimulating CM proliferation and/or protection with TT-10 might complement current therapies for MI.
Summary Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C11H10FN3OS2) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction–induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.