Developing novel flavonoid senolytics through phenotypic drug screening and drug design

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. Primary mouse embryonic fibroblasts (MEFs) cells were used. WT MEFs non-senescent (proliferative control) and WT MEFs induced to senescence by oxidative stress (H2O2) and genotoxic stress (etoposide). Cells were treated with two novel flavonoid analogs, SR29384 and SR31133 for 12 hours. 3 biological replicates per group.