Discovery of small molecule modulators of the thin filament that alter the contractile profile in a hypertrophic cardiomyopathy engineered tissue model

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Underlying both cardiomyopathies and heart failure is the alteration of the contractile profile of the myocardium leading to impairments in force generation (i.e., systolic function) or relaxation kinetics (i.e., diastolic function) of the sarcomere. Fundamental studies of the sarcomeric unit of striated muscle as well as significant genetic evidence from hereditary cardiomyopathies have implicated the thin filament complex as a key multi-protein complex tightly regulating contraction and relaxation kinetics in cardiac muscle. Utilizing affinity selection mass spectrometry high-throughput screening, we set out to identify small-molecules that bind to the cardiac thin filament and result in calcium desensitization in reconstituted biochemical and tissue-isolated myofibril systems. Through chemical optimization to improve potency and solubility, we further developed a series and were able to confirm target engagement with intact reconstituted cardiac thin filaments using isothermal calorimetry. Optimization of several absorption, distribution, metabolism, and excretion properties provided exemplar compounds that in matrixed tension assays using mouse skinned fibers showed diverse antagonist and desensitization profiles. Two of these compounds with mixed desensitization-antagonist profiles were further tested in an engineered heart tissue model of hypertrophic cardiomyopathy and were confirmed to demonstrate mixed pharmacology with impacts on max force contraction and relaxation kinetics from the contracted to relaxed state. Together these studies provide a starting point for future efforts to develop selective, thin filament-targeted small molecules that potentially provide a new mechanism for treatment of heart failure.

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