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

AIMS: Impaired SUMOylation of the sarcoplasmic/endoplasmic reticulum Ca METHODS AND RESULTS: Through structure-activity relationship (SAR) screening of 100 analogs, SC023 was identified as the lead candidate. SC023 demonstrated 1.5-fold higher in vitro SUMO E1 hydrolysis activity than N106 and dose-dependently enhanced SERCA2a SUMOylation, contractility, and calcium handling in isolated adult cardiomyocytes. SC023 exhibited significantly improved metabolic stability, with a 2.7-fold longer half-life in human hepatocytes and 14.4-fold longer oral half-life in mice compared with N106. In a murine transverse aortic constriction model, chronic oral administration of SC023 for one month significantly restored left ventricular systolic function and attenuated adverse remodeling. Mechanistically, SC023 targets the SUMO E1 enzyme to trigger intrinsic SERCA2a SUMOylation without altering SUMO-related regulatory enzymes. Importantly, safety profiling confirmed that SC023 exhibited reduced off-target activity, specifically lacking the adenosine A2A and serotonin 5-HT2B receptor inhibition observed with N106. CONCLUSIONS: SC023 is a potent, metabolically stable second-generation SERCA2a SUMOylation enhancer that overcomes the PK and safety limitations of N106. Sustained pharmacological enhancement of SERCA2a SUMOylation by SC023 represents a promising therapeutic strategy for restoring calcium homeostasis and cardiac function in HF.