Discovery of Novel Synthetic Cyclohexene-Based Small Molecules Targeting Senescence against Age-Related Pulmonary Fibrosis

Targeting cellular senescence has emerged as a therapeutic strategy for the increasingly prevalent age-related diseases, yet no drugs have reached clinical approval specifically as senotherapeutics. Through senescence-phenotype screening of our recently generated human microbiota-inspired library of small molecules, we identified a tetrasubstituted cyclohexene as a novel bioactive chemotype. Following the synthesis of related analogues and their evaluation in relevant models of senescence, we discovered compound 25 (UCM-17017) that decreases β-galactosidase activity in senescent human fibroblasts and selectively reduces the viability of senescent human lung adenocarcinoma cells over proliferative cells. The new senolytic compound exhibits a favorable pharmacokinetic profile in vivo and induces a beneficial effect in a mouse model of pulmonary fibrosis, a senescence-related disease with significant unmet medical needs. Our results are valuable for senotherapeutic drug discovery and support the interest of targeting cellular senescence as a promising approach against age-related pulmonary fibrosis.