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Developing novel flavonoid senolytics through phenotypic drug screening and drug design

ABSTRACT: The discovery of effective senolytics offers a promising approach for treating many age-related diseases. In this study, we employed a phenotypic drug discovery approach, combining drug screening and drug design, to identify and develop novel senolytic agents based on the flavonoid fisetin. We successfully developed two novel flavonoid analogs, SR29384 and SR31133, which demonstrated significantly enhanced senolytic activities compared to fisetin. These analogs showed broad-spectrum efficacy in eliminating various senescent cell types, reducing tissue senescence, extending healthspan in mice, and prolonging lifespan in Drosophila. Through RNA sequencing, machine learning, and computational screening, our mechanistic studies suggest that these novel flavonoid senolytics may target PARP1, BCL2L1, and CDK2 to induce senescent cell death.

ORGANISM(S): Mus musculus

PROVIDER: GSE279349 | GEO | 2024/10/27

REPOSITORIES: GEO

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Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.

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Developing novel flavonoid senolytics through phenotypic drug screening and drug design

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