Problem

Cardiomyopathy weakens the heart muscle and impairs its ability to pump blood effectively, often leading to heart failure or sudden cardiac death. While doxorubicin remains an essential component of many cancer regimens, its use is limited by the risk of causing lethal cardiomyopathy. A major contributor to this condition is defective mitophagy, the failure to clear damaged mitochondria. Despite its importance, there are currently no therapies that directly restore mitochondrial quality control

Solution

• Researchers at The Ohio State University have characterized ST-539, a small-molecule inhibitor of USP30, which is an outer mitochondrial membrane protein that negatively regulates PINK1/Parkin-dependent mitophagy by removing ubiquitin from mitochondrial proteins, thereby preventing their degradation
• ST-539 promotes the clearance of mitochondria in response to mitochondrial depolarizing agents while only marginally altering mitochondrial function in vitro
• ST-539 reduces doxorubicin-induced cell death in Human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs)
• Pharmacological inhibition of USP30 increases cardiac mitophagy without damaging the cardiac function in mice. Of note, mitophagic flux in liver or the hippocampus of the brain remains unchanged following the ST-539 administration

Applications

• Use of USP30 inhibitors in combination with chemotherapeutic agents (such as doxorubicin) to improve efficacy and ensure cardioprotection
• Use of ST-539 to prevent and treat cardiomyopathy by enhancing mitochondrial quality control in heart tissue

Advantages

• Novelty: the invention addresses a new therapeutic target (USP30) not currently exploited by approved drugs
• Target specificity: ST-359 selectively inhibits USP30 enzyme function and induces activation of mitophagy without broadly affecting healthy mitochondria
• Small molecule: the modality enables versatile administration routes, including oral and injectable
• Potential for combination therapies: the small molecule USP30 inhibitor can be used in combination with chemotherapeutic drugs to enhance cancer treatment

Seeking opportunities for out-licensing and collaboration