Discovery of a novel chalcone-derived covalent Keap1 binder for mitigating cisplatin-induced mitochondrial dysfunction and nephrotoxicity.

ABSTRACT: Cisplatin-induced kidney injury (CIKI) is a major adverse effect of this widely used chemotherapy agent. Targeting key events involved in CIKI, such as inflammation, apoptosis, mitochondrial dysfunction and oxidative stress, holds potential for mitigating CIKI and improving patient outcomes. Herein, we report a novel N-containing chalcone derivative as a cysteine-targeting covalent binder of Keap1, which effectively mitigate cisplatin (CDDP)-induced mitochondrial dysfunction (CIMD) and CIKI through activating Keap1-Nrf2-ARE signaling. Initially, a chalcone derivative (A6) was identified as a strong Nrf2 agonist through high-throughput luminescence screening of in-house compounds. After two rounds of structural optimization, we developed a novel N-containing chalcone derivative (C5), which

SUBMITTER: Deng Y 

PROVIDER: S-EPMC12270011 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature