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.

Keywords: cardiomyopathy; contractility; crossbridge cycle; drug trials; sarcomere; therapeutics.

Figure 1

Five potential therapeutic targets in the contractile apparatus for small molecules. Original figure was made by using BioRender.com. The availability of myosin heads for interaction can be ameliorated via myosin activators or alleviated by myosin inhibitors. Similarly, affinity of troponin C towards Ca²⁺ ions can be increased (Ca²⁺-sensitisers) or decreased (Ca²⁺-desensitisers). Protein kinase A (PKA)-dependent phosphorylation of TnI was found to be lost in some forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), but it can be restored via Recouplers. Figure was created by using Biorender.com.

Figure 2

Assessment of therapeutic potential of small molecules that act on the contractile apparatus. Searches of the literature yielded 21 compounds worth further consideration. The compounds were evaluated and scored according to eight different criteria summarised in the figure. Created by using Venngage infographic maker.

Figure 3

The chemomechanical crossbridge cycle and its regulation via troponin–tropomyosin (thin filament state) and super-relaxed/disordered-relaxed (SRX/DRX) equilibrium. The crossbridge is represented in the blue circle. The availability of actin-binding sites is regulated by the state of thin filament (top left). The equilibrium between blocked (no myosin bound) and closed (weak myosin-binding) is controlled by Ca²⁺. Myosin heads regulate the closed-open state in a cooperative fashion. Only thin filament in open state can participate in the chemomechanical cycle. Two small molecules that interact with both transitions are illustrated. The availability of myosin heads is regulated by the SRX/DRX equilibrium, and only myosin heads in DRX can be part of the crossbridge cycle. Four small molecules can regulate the transition, as shown. Figure was created by using Biorender.com as a modified version from References [65,83].