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Vincere Biosciences is at the forefront of developing innovative treatments for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD). Our novel therapeutic USP30 inhibitors are engineered to enhance mitophagy, the selective removal of damaged mitochondria. This process is crucial, as impaired mitophagy aggravates AKI and CKD. Vincere has molecules optimized for tissue-specific exposure in the kidney poised to meet the urgent need for renal protection, attenuating AKI severity and fostering recovery.
Molecules target the Pink1/parkin/USP30 pathway, pivotal in damage-induced mitophagy with over 700 synthesized compounds optimized for a range of pharmacokinetic profiles. Lead molecules demonstrate potent USP30 inhibition in vitro, assessed via mass spectrometry/MALDI-TOF and fluorescence-based assays, exhibiting low nanomolar potencies with high specificity for USP30, established against 40+ deubiquitinating enzymes (DUBs), showed over 80-fold preference for USP30, reducing off-target risks. In vivo pharmacokinetics in rats and mice confirmed effective renal concentration at therapeutic levels.
Renal candidate molecules effectively enhanced mitophagy across various human cell lines, maintaining cell health and mitochondrial integrity. In several models of AKI, USP30 inhibitors reduced severity in a dose-dependent manner when administered as both a pre-treatment and post-injury treatment.
These findings highlight Vincere’s USP30 inhibitor molecules potential in AKI treatment and as a prophylactic measure against CKD progression. The mitophagy-enhancing ability, coupled with selectivity and favorable pharmacological profile present a promising therapeutic approach in AKI management and CKD prevention.