Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Abstract

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as “recouplers” was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.

Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

“…Mavacamten (MAVA), formerly known as , is an allosteric inhibitor of sarcomeric myosins identified in a small-molecule screening of potential drugs for the treatment of human hypertrophic cardiomyopathy (HCM; Green et al, 2016;Spudich et al, 2016;Alsulami and Marston, 2020). In the last 10 yr, a lot of experimental evidence has supported the hypothesis that HCM could mainly result from an increase in the availability of myosin heads for entering the actomyosin chemomechanical cycle (Spudich, 2014;Garfinkel et al, 2018;Trivedi et al, 2018;Spudich, 2019) associated with a shift from the so-called autoinhibited or super-relaxed (SRX) state (Stewart et al, 2010;Hooijman et al, 2011;Alamo et al, 2017) to a disordered-relaxed (DRX) state (McNamara et al, 2015).…”

Functional Role of Class III Myosins in Hair Cells

“…It is important to understand how these mutations alter the conserved mechanism of force generation in myosins. Recently, small molecule allosteric regulators of myosin have been successfully developed to treat heart disease, suggesting this strategy may be successful for treating other myosin-associated disease conditions ( Malik et al, 2011 ; Green et al, 2016 ; Alsulami and Marston, 2020 ).…”

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

“…Clinical trials on several sarcomere contractility modulators showed moderate improvement in cardiac function (recently reviewed in [ 196 ]). Moreover, the adverse events caused by these drugs necessitates the development of analogous that are better tolerated.…”