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Published on: May 28, 2014
Discovery of a novel chalcone-derived covalent Keap1 binder for mitigating cisplatin-induced mitochondrial
Yanyan Deng1, Leizhi Xu1, Zhengtao Jiang1
1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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 exhibits enhanced Nrf2 agonist activity, favorable drug-like properties, and improved renal-targeting ability. Cellular and animal studies showed that C5 significantly ameliorated CIMD and CIKI in CDDP-induced nephrocytes and CIKI mice via activating the Keap1-Nrf2-ARE signaling pathway in both settings. Mechanistically, C5 covalently modified Keap1 on two critical functional cysteines in Keap1 (Cys288 in the IVR domain and Cys319 in the Kelch domain), synergistically amplifying Nrf2 activation. As an extremely potent Nrf2 agonist, C5 mitigated CIKI by orchestrating antioxidant defenses, boosting mitochondrial energetics, promoting mitochondrial biogenesis, restoring mitochondrial dynamics, and inhibiting subsequent apoptotic cascade activation. Furthermore, Nrf2 knockdown markedly attenuated the nephroprotective effects of C5 in CIKI mice, confirming the critical role of Keap1-Nrf2 signaling in its nephroprotective mechanism. Collectively, a novel N-containing chalcone derivative was developed as an efficacious and renal-targeting covalent binder of Keap1, offering a promising therapeutic candidate for combating CIKI.
Insights
A novel chalcone derivative (C5) effectively protects against cisplatin-induced kidney injury (CIKI) by targeting Keap1 and activating the Nrf2 pathway. This compound mitigates mitochondrial dysfunction and inflammation, offering a promising therapeutic strategy for CIKI.
Area of Science:
- Biochemistry
- Pharmacology
- Nephrology
Background:
- Cisplatin chemotherapy can cause significant kidney injury (CIKI), a major clinical challenge.
- Key pathological events in CIKI include inflammation, apoptosis, mitochondrial dysfunction, and oxidative stress.
- Targeting these pathways offers a potential strategy to mitigate CIKI and improve patient outcomes.
Purpose of the Study:
- To develop a novel therapeutic agent for mitigating cisplatin-induced kidney injury (CIKI).
- To investigate the mechanism of action of a novel N-containing chalcone derivative (C5) as a Keap1 covalent binder and Nrf2 activator.
- To evaluate the efficacy of C5 in ameliorating cisplatin-induced mitochondrial dysfunction (CIMD) and CIKI.
Main Methods:
- High-throughput screening identified a chalcone derivative (A6) as an Nrf2 agonist.
- Structural optimization led to the development of a novel N-containing chalcone derivative (C5) with enhanced properties.
- In vitro cellular studies and in vivo animal models (CIKI mice) were used to assess the nephroprotective effects of C5.
- Mechanistic studies involved assessing Keap1 covalent modification, Nrf2 activation, mitochondrial function, and apoptosis markers.
Main Results:
- Compound C5 demonstrated enhanced Nrf2 agonist activity, favorable drug-like properties, and improved renal targeting.
- C5 significantly ameliorated CIMD and CIKI in both cellular and animal models by activating the Keap1-Nrf2-ARE signaling pathway.
- C5 covalently modified Keap1 at Cys288 and Cys319, leading to synergistic Nrf2 activation.
- C5 mitigated CIKI by orchestrating antioxidant defenses, boosting mitochondrial energetics, promoting biogenesis, restoring dynamics, and inhibiting apoptosis.
- Nrf2 knockdown attenuated the protective effects of C5, confirming the pathway's critical role.
Conclusions:
- A novel N-containing chalcone derivative (C5) acts as an effective renal-targeting covalent binder of Keap1.
- C5 mitigates CIKI and CIMD through potent activation of the Keap1-Nrf2-ARE pathway.
- This compound represents a promising therapeutic candidate for preventing and treating cisplatin-induced kidney injury.
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