Cardiac myosin activation part 1: from concept to clinic

Area of Science:

• Cardiovascular Research
• Pharmacology
• Molecular Biology

Background:

• Systolic heart failure is characterized by decreased cardiac contractility, with limited therapeutic options.
• Current contractility-enhancing drugs act indirectly via signaling pathways, often causing adverse effects.
• Direct sarcomere activation presents a potential alternative to overcome existing drug limitations.

Purpose of the Study:

• To identify and develop novel small molecules that directly activate cardiac myosin.
• To evaluate the efficacy and mechanism of cardiac myosin activators in preclinical and clinical models.
• To explore cardiac myosin activation as a therapeutic strategy for systolic heart failure.

Main Methods:

• Screening of a small molecule library using a reconstituted cardiac sarcomere model.
• Iterative optimization of identified compound classes, leading to omecamtiv mecarbil.
• Assessment of cardiac function and myocyte calcium homeostasis in animal models and initial human studies.

Main Results:

• Identification of direct cardiac myosin activators, with omecamtiv mecarbil as the lead compound.
• Omecamtiv mecarbil accelerates myosin's force-generating transition without altering calcium homeostasis.
• Preclinical studies showed increased cardiac function; early clinical trials confirmed human efficacy.

Conclusions:

• Direct cardiac myosin activation represents a novel mechanism for improving cardiac contractility.
• Omecamtiv mecarbil demonstrates potential as a targeted therapy for systolic heart failure.
• Further clinical investigation is warranted for acute and chronic heart failure treatment.