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Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
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RMC-6272, a selective third-generation bi-steric mTORC1 inhibitor, improves cardiac function in pressure
Mariam Rogge1,2, Johannes Fischer1,2, Tobias Jakobi3
1Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, 69120, Heidelberg, Germany.
Summary
A new drug, RMC-6272, effectively inhibits mTORC1, preventing and treating heart failure in mice. This selective inhibitor shows promise for heart disease therapy by protecting cardiomyocytes from pathological remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pharmacology
Background:
- Heart failure involves pathological cardiomyocyte remodeling driven by mechanistic target of rapamycin complex 1 (mTORC1) overactivation.
- Current mTOR inhibitors have limitations, including incomplete mTORC1 inhibition and detrimental off-target effects on mTORC2 signaling.
Purpose of the Study:
- To evaluate the therapeutic potential of RMC-6272, a novel bi-steric mTORC1 inhibitor, in preclinical models of pressure overload-induced heart failure.
- To assess the potency and selectivity of RMC-6272 against existing mTOR inhibitors.
Main Methods:
- RMC-6272's potency and selectivity were tested in isolated cardiomyocytes and compared to rapamycin and Torin1.
- Cardiac hypertrophy was induced in vitro using phenylephrine and in vivo using aortic banding.
- Cardiomyocyte-specific mRNA translation was analyzed in αMHC-Cre Ribo-tag mice.
Main Results:
- RMC-6272 exhibited superior potency and specificity for mTORC1 inhibition compared to rapamycin and Torin1.
- RMC-6272 prevented in vitro hypertrophic growth and suppressed mTORC1-dependent mRNA translation.
- Preventive RMC-6272 treatment preserved cardiac function in pressure overload models; therapeutic treatment improved established hypertrophy.
Conclusions:
- RMC-6272 effectively inhibits mTORC1, offering protection against pathological cardiac remodeling and dysfunction.
- This third-generation inhibitor demonstrates significant therapeutic potential for heart failure, even after disease onset, with improved selectivity over existing drugs.
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