Abstract

Senescent cells are present at cancerous and fibrotic tissues and are associated with multiple age-related diseases. Recently, drugs that selectively kill senescent cells, termed senolytics, have proven beneficial in improving the outcomes of many of these pathologies. To identify novel senolytic compounds, we have screened libraries comprising ~2,000 small molecules using systems of oncogene-induced and therapy-induced senescence. We have assessed the senolytic effect of these compounds in different cell types and in response to different senescent inducers. Interestingly, we observed that while some compounds have just selectivity to kill cells undergoing oncogene-induced senescence, others behaved as broad-spectrum senolytics. Despite the potential of this drug-repurposing approaches, our knowledge of the molecular pathways that affect the survival of senescent cells is still limited. To discover novel senolytic targets, we have also performed RNAi screens and identified novel liabilities of senescent cells. Here, we will show our progress on validation of some of these small molecules and targets across different senescence models.