Novel first-in-class drug candidate protects from ischemia-reperfusion injury by targeting the SERCA2 complex

Abstract The prevalence and incidence of heart failure (HF) have shown a consistent increase over the last years, and 50-60% of HF patients have a history of myocardial infarction (MI). MI affects 7 million people globally every year. It’s essential to reduce infarct size and protect the myocardial tissue at risk, as this is one of the most significant predictors of post-MI HF. There is a significant unmet medical need for cardioprotection during MI treatment. 13M is our novel first-in-class drug candidate in preclinical development for the treatment of ischemia-reperfusion injury (IRI). We are targeting the molecular complex of sarcoplasmic reticulum calcium ATPase (SERCA2) at the level of the AKAP18δ-PLB interaction. During adrenergic stimulation, activation of cAMP-dependent protein kinase A (PKA) causes phosphorylation phospholamban (PLB), and its ability to inhibit SERCA2 is lost. The A-kinase anchoring protein (AKAP) 18g/d, which holds PKA and PLB in close proximity, facilitates the discrete control of PLB phosphorylation. High-throughput screening and subsequent processing of hits identified a series of small molecule PPI disruptors. 13M was selected as the most promising candidate after in-depth testing by a combination of biochemistry, electrophysiology in vitro experiments, demonstrating that the compound exclusively blocks the adrenergic effect on SERCA2. Thus, 13M is shown to be a highly selective modulator of the SERCA2 pump in the heart by targeting the AKAP18g/d-PLB protein-protein interaction. Additionally, in preclinical pharmacology studies, our drug candidate, 13M, has shown a negative inotropic effect in vivo in an adrenergic isoproterenol animal model without affecting the chronotopic effect of adrenergic stimulation. In a large-animal IRI model, 13M showed the ability to reduce the infarct size, improving heart functionality post-acute myocardial infarction. Therefore, through its unique and heart-specific mechanism of action, 13M is a promising new drug candidate for the treatment of acute myocardial infarction in connection with percutaneous coronary intervention.