Design and Synthesis of Senescence-Targeted Prodrugs with Senomorphic and Senolytic Properties To Mitigate Chemotherapy-Induced Kidney Injury

Senotherapeutic agents hold great potential for mitigating chemotherapy-induced kidney injury. However, the heterogeneity of cellular senescence complicates their application, as early stage senescent cells (SnCs) play beneficial roles in kidney damage repair. Senotherapeutics are broadly categorized into two classes: senolytics, which selectively eliminate SnCs, and senomorphics, which suppress the senescence-associated secretory phenotype (SASP) without killing them. Herein, we repurposed an antioxidant agent, bardoxolone methyl (CDDOMe), as a novel senomorphic agent to mitigate the chemotherapy-induced kidney injury and subsequently modified it into a series of senescence-associated β-galactosidase (SA-β-gal) activated prodrugs. The optimal prodrug, <b>Gal-CDD-01</b>, selectively induced apoptosis of the late-staged SnCs, while suppressing the senescence progression of early staged SnCs. Notably, <b>Gal-CDD-01</b> possesses favorable efficacy and distribution selectivity in vivo, resulting in amelioration of motor functions in mice with kidney injury. Overall, this study presents a rational design for a dual-functional senescence-targeted prodrug and also explores its potential application in treating the chemotherapy-induced kidney injury.