Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases
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...
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9599 |
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| author | Khulud Alsulami Steven Marston |
| author_facet | Khulud Alsulami Steven Marston |
| author_sort | Khulud Alsulami |
| collection | DOAJ |
| description | 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 (Ca<sup>2+</sup>-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. |
| first_indexed | 2024-03-10T14:01:07Z |
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| language | English |
| last_indexed | 2024-03-10T14:01:07Z |
| publishDate | 2020-12-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-81293c85b95e4d9088426c798ad317932023-11-21T01:09:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124959910.3390/ijms21249599Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle DiseasesKhulud Alsulami0Steven Marston1Imperial Centre for Translational and Experimental Medicine, Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London W12 0NN, UKImperial Centre for Translational and Experimental Medicine, Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London W12 0NN, UKHypertrophic 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 (Ca<sup>2+</sup>-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.https://www.mdpi.com/1422-0067/21/24/9599contractilitysarcomerecardiomyopathycrossbridge cycletherapeuticsdrug trials |
| spellingShingle | Khulud Alsulami Steven Marston Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases International Journal of Molecular Sciences contractility sarcomere cardiomyopathy crossbridge cycle therapeutics drug trials |
| title | Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases |
| title_full | Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases |
| title_fullStr | Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases |
| title_full_unstemmed | Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases |
| title_short | Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases |
| title_sort | small molecules acting on myofilaments as treatments for heart and skeletal muscle diseases |
| topic | contractility sarcomere cardiomyopathy crossbridge cycle therapeutics drug trials |
| url | https://www.mdpi.com/1422-0067/21/24/9599 |
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