IND-enabling studies of a USP30 inhibitor for acute kidney injury

The National Institute of Diabetes and Digestive and Kidney Diseases awarded $1,297,479 to Vincere Biosciences, Inc. on August 28, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct IND-enabling studies of small molecule USP30 inhibitors for acute kidney injury treatment.

Vincere will advance multiple USP30 inhibitor molecules through IND-enabling studies to support clinical development for acute kidney injury, particularly cardiac surgery-associated AKI. The work builds on prior research demonstrating that the selected molecules enhance mitophagy—the cellular clearance of damaged mitochondria—in renal cell models and improve renal function in vivo across three AKI models: rhabdomyolysis, ischemic reperfusion injury, and cisplatin-induced nephrotoxicity. The molecules exhibit high potency against USP30, selective activity over other deubiquitinases and unrelated targets, and favorable in vitro ADME properties and pharmacokinetic profiles in rodents. Current treatment for acute kidney injury is limited to supportive care with no disease-modifying therapies available to prevent progression to chronic kidney disease or end-stage renal disease.

Performance occurs in Cambridge, Massachusetts, with a period of performance extending through May 31, 2028. The award is assistance type Project Grant, with $1,297,479 obligated.

Abstract

Existing treatments for acute kidney injury (AKI) are limited to supportive care, and there are no current therapies that can modify the disease course or prevent progression to chronic kidney disease (CKD) and ultimately end-stage renal disease (esrd). While AKI has multiple causes, cardiac surgery-associated AKI (CSA-AKI) is a major etiology. Evidence indicates that damaged mitochondria accumulate in AKI, contributing significantly to the pathogenesis of the condition. And that impaired mitophagy - the cellular process for clearance of damaged mitochondria - drives the accumulation. Mitophagy is enhanced by the PINK1/parkin pathway and decreased by the deubiquitinase (DUB) USP30. Inhibition or knockdown of USP30 can enhance mitophagy in various cell types and confers protection against kidney injury in multiple AKI models, including ischemia-reperfusion injury (IRI), cisplatin-induced nephrotoxicity, and rhabdomyolysis. We have synthesized 900+ small molecule USP30 inhibitors (USP30I) and characterized a subset for potency, pharmacokinetics, adme, and efficacy. This work has led to selection of multiple viable molecules with optimal properties for progression through IND-enabling studies and toward clinical development. Our preliminary data demonstrate vincere's molecules are able to improve renal function in vivo in 3 models of AKI (rhabdomyolysis, ischemic reperfusion injury, and cisplatin-induced injury). These molecules have high potency against USP30 in vitro and the ability to enhance mitophagy in renal cells without cytotoxicity. The data also demonstrate high selectivity over other dubs and a panel of unrelated targets, overcoming challenges of prior programs. Vincere's USP30I molecules exhibit excellent in vitro adme properties and favorable pharmacokinetic profiles in rodents. In this direct phase II application, we will conduct studies necessary to advance a selected development candidate (DC) USP30I toward submission of an investigational new drug (IND) application. This project has 3 aims: aim 1 involves genotoxicity assessment for the selected DC and acute/short-term toxicology in two species. Next, aim 2 involves 28-day GLP toxicology in two species. In aim 3 cardiovascular, respiratory, and central nervous system safety will be assessed. Assuming favorable results from this work, we will submit an IND application and thereafter initiate a first-in-human study. In parallel with the project, we will continue to nurture relationships with larger pharmaceutical companies and financing partners to facilitate clinical development and commercialization.