Vincere Biosciences has proprietary USP30 inhibitor small molecules being optimized in vivo towardsdevelopment candidates for heart failure (HF) and cardiac aging. HF is an age-related disorder mechanisticallyrooted in the decline of mitochondrial quality control mechanisms in myocardial cells which leads to increasedinflammation and senescence with decreased myocardial cell turnover. Despite strong rationale for theinvolvement of mitochondrial dysfunction and mitophagy, there have been no efforts in clinical trials to enhancemitophagy as a therapeutic approach for cardiac aging. Enhancement of mitophagy via knockdown of USP30 orincrease in parkin reduces myocardial cell senescence in an aging model of heart disease both in primarycardiomyocytes and in adult rat and mouse myocardial cells in vivo. In light of this compelling evidence thatincreased mitophagy may provide benefit for cardiac aging, we are compelled to test our USP30 inhibitorcompounds in relevant models.Our preliminary data demonstrate that we have developed proprietary compounds with low nanomolar in vitropotency for USP30 inhibition as measured using two orthogonal methods. The compounds are cell-penetrantand enhance mitophagy in the presence of antimycin/oligomycin (A/O) in human cells with endogenousexpression of USP30, parkin, and substrates. Importantly, compounds do not damage or depolarize healthymitochondria as measured by TMRE. Candidate lead-like compounds are highly selective when tested againsta panel of over 40 deubiquitinating enzymes using two orthogonal assays. We have profiled compounds forvarious ADME properties and successfully optimized properties including solubility, permeability, microsomalstability, and plasma protein binding. Our lead compound has an excellent PK profile in rat and mouse andpenetrates the heart at sustained levels well above 2x the compounds' low nM IC50. The following Aims test thehypothesis that our selective USP30 inhibitors can reduce senescence in cell and animal models of cardiacaging.Aim 1: Determine whether USP30 inhibitors can reduce cell senescence in primary myocardial cellsWe will treat neonatal mouse myocardial cells with USP30 inhibitor/vehicle control in a D-Gal model to determinewhether the small molecule inhibitors can reduce cellular senescence in culture.Aim 2: Assess the effects of USP30 inhibition on D-gal induced myocardial cell senescence in vivo .We will evaluate whether inhibition of USP30 can reduce the deficits induced by D-gal, including mitochondrialdysfunction, cellular senescence, and inflammatory markers. We will treat mice with daily D-gal injections, withor without co-administration of USP30 inhibitor for 8 weeks to induce senescence. We will evaluate the effect ofcompound on multiple markers of mitochondrial function, senescence, and inflammation.
Public Health Relevance Statement: NARRATIVE
Heart failure is a widespread age-related problem that results in a tremendous burden on people's lives and on
the healthcare system and for which, currently, no treatments exist to prevent this deadly condition. This project
seeks to study the effect of a novel drug on non-clinical models of cell senescence, a phenomenon thought to
contribute to heart failure.
Project Terms: <21+ years old>|
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