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, Gal-CDD-01,
selectively induced apoptosis of the late-staged SnCs, while suppressing
the senescence progression of early staged SnCs. Notably, Gal-CDD-01 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.