Abstract
Small molecules that modulate myofibril ATPase activity via the myosin regulatory light chain (RLC) display a broad spectrum of activity in their ability to enhance relaxation and slow contraction. EDG-7500 exhibits features consistent with a ‘diastolic-selective’ cardiac sarcomere modulator (d-CSM), and its ability to treat HCM was explored in engineered human tissue (EHT), human HCM cardiac strips, and an R403Q mutation swine model. In fibers, EDG-7500 preferentially inhibited myofibril ATPase activity and force at diastolic calcium levels, retained length-dependent force activation, accelerated relaxation, and exhibited a shallow, self-limiting inhibitory-exposure response to LV fractional shortening. Compared to CMIs, EDG-7500 moved myosin heads towards the thin filament and accelerated relaxation without decreasing force in mutated EHTs (R403Q). In human HCM cardiac strips, EDG-7500 did not alter myosin SRX state, but decreased Ca2+-sensitivity of force independent of mutation. In R403Q swine, chronic EDG-7500 normalized LV filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function and cardiac reserve. EDG-7500 differentiates itself from CMIs by uniquely targeting both phases of the cardiac cycle, improving ventricular relaxation while preserving systolic function. This suggests optimal diastolic efficacy can be reached without balancing systolic impairment.
Authors
Craig A. Emter, Marcus Henze, Mike DuVall, Sarah Lehman, Lindsey Lee, Ben Barthel, Natalie A. Hawryluk, Molly Madden, Yangsong Wu, Amy Perry, Martin Beyer, Eric Wei, Cassady Rupert, Steve Roof, Angela Peter, Emily DiNatale, Sara Cantrell, Jessica Tolley, Stephen Schlachter, Jolanda van der Velden, Michelle Michels, Christine Seidman, Weikang Ma, Leslie Leinwand, Stuart Campbell, Julien Ochala, David Bluemke, Darla Tharp, Jonathan Seidman, Carlos L. del Rio, Marc Semigran, Marc Evanchik, Kevin Koch, Alan Russell
Figure 1
Biochemical assessment of EDG-7500 and EDG-7499 demonstrates preferential inhibition of myofibril ATPase activity at diastolic calcium concentrations and mechanistic action through indirect modulation of enzymatic activity that requires the regulatory light chain (RLC).
