A metabolically stable second-generation SERCA2a SUMOylation enhancer improves cardiac function in heart failure

Area of Science:

• Cardiology
• Biochemistry
• Pharmacology

Background:

• Impaired SUMOylation of SERCA2a contributes to heart failure (HF) by disrupting calcium cycling and contractility.
• The first-generation enhancer N106 showed promise but had limitations in metabolic stability and half-life.
• Developing improved analogs is crucial for effective therapeutic strategies in HF.

Purpose of the Study:

• To develop SC023, a second-generation analog of N106, with enhanced pharmacokinetic properties and therapeutic efficacy for heart failure.
• To evaluate the efficacy and safety of SC023 in preclinical models of cardiac dysfunction.

Main Methods:

• Structure-activity relationship screening identified SC023 from 100 analogs.
• In vitro assays assessed SUMO E1 hydrolysis and SERCA2a SUMOylation.
• Pharmacokinetic studies evaluated half-life in hepatocytes and mice.
• In vivo studies used a murine transverse aortic constriction model to assess cardiac function and remodeling.
• Safety profiling examined off-target receptor activity.

Main Results:

• SC023 demonstrated superior in vitro SUMO E1 hydrolysis and dose-dependent enhancement of SERCA2a SUMOylation, contractility, and calcium handling.
• SC023 exhibited significantly improved metabolic stability and longer half-lives compared to N106.
• Chronic oral SC023 administration restored cardiac function and attenuated adverse remodeling in a HF mouse model.
• SC023 targets the SUMO E1 enzyme, enhancing SERCA2a SUMOylation without affecting other regulatory enzymes.
• SC023 showed reduced off-target activity, notably lacking inhibition of adenosine A2A and serotonin 5-HT2B receptors.

Conclusions:

• SC023 is a potent, metabolically stable SERCA2a SUMOylation enhancer that overcomes the limitations of N106.
• Pharmacological enhancement of SERCA2a SUMOylation via SC023 offers a promising therapeutic approach for heart failure.
• SC023 has the potential to restore calcium homeostasis and improve cardiac function in HF patients.