Virtual drug screen reveals context-dependent inhibition of cardiomyocyte hypertrophy

Abstract

Background and PurposePathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac remodeling, the therapeutic space that targets hypertrophy is limited. Here, we apply a network model to virtually screen for FDA-approved drugs that induce or suppress cardiomyocyte hypertrophy. Experimental ApproachA logic-based differential equation model of cardiomyocyte signaling was used to predict drugs that modulate hypertrophy. These predictions were validated against curated experiments from the prior literature. The actions of midostaurin were validated in new experiments using TGF{beta}- and NE-induced hypertrophy in neonatal rat cardiomyocytes. Key ResultsModel predictions were validated in 60 out of 70 independent experiments from the literature and identify 38 inhibitors of hypertrophy. We additionally predict that the efficacy of drugs that inhibit cardiomyocyte hypertrophy is often context dependent. We predicted that midostaurin inhibits cardiomyocyte hypertrophy induced by TGF{beta}, but not NE, exhibiting context dependence. We further validated this prediction by in vitro experimentation. Network analysis predicted critical roles for the PI3K and RAS pathways in the activity of celecoxib and midostaurin, respectively. We further investigated the polypharmacology and combinatorial pharmacology of drugs. Brigatinib and irbesartan in combination were predicted to synergistically inhibit cardiomyocyte hypertrophy. Conclusion and ImplicationsThis study provides a well-validated platform for investigating the efficacy of drugs on cardiomyocyte hypertrophy, and identifies midostaurin for consideration as an antihypertrophic drug. What is already known- Cardiac hypertrophy is a leading predictor of heart failure. - Cardiomyocyte hypertrophy is driven by intracellular signaling pathways that are not targeted by current drugs What this study adds- Computational model integrates 69 unique drugs to predict cardiomyocyte hypertrophy - Drug-induced inhibition of cardiomyocyte hypertrophy is context-dependent - Midostaurin inhibits TGF{beta}-induced cardiomyocyte hypertrophy Clinical significance- Midostaurin is identified as a candidate antihypertrophic drug - Several FDA approved drugs are predicted to inhibit cardiomyocyte hypertrophy either individually or in combination.