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Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small
Hui Ren1, Yu-Jue Wang1, Xin-Ye Wang1
1Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Abstract:
Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug 5u exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS. The active compound 6a released from 5u covalently binds to Cys475 and Sec498 sites on TrxR1, resulting in inhibition on TrxR1 activity, which led to redox homeostasis disorder, and caused apoptosis and ferroptosis. Moreover, prodrug 5u exhibited significant antitumor efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered prodrug 5u as a novel TrxR1 inhibitor for the treatment of NSCLC and provide a promising strategy of ROS-activated prodrug for covalent compounds in cancer therapy.
Insights
A novel prodrug, 5u, targets thioredoxin reductase 1 (TrxR1) in non-small cell lung cancer (NSCLC). This reactive oxygen species (ROS)-activated compound effectively inhibits TrxR1, leading to cancer cell death and demonstrating significant antitumor effects.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Thioredoxin reductase 1 (TrxR1) is overexpressed in non-small cell lung cancer (NSCLC), making it a key therapeutic target.
- Traditional sesquiterpene lactones with α-methylene-γ-lactone moieties are susceptible to rapid metabolism by endogenous nucleophiles, limiting their therapeutic efficacy.
- Developing stable prodrugs that release active compounds specifically in the tumor microenvironment is crucial for effective cancer therapy.
Purpose of the Study:
- To design and synthesize novel thioether derivatives as reactive oxygen species (ROS)-triggered prodrugs for NSCLC treatment.
- To overcome the metabolic instability of α-methylene-γ-lactone compounds.
- To evaluate the efficacy of a ROS-triggered prodrug strategy for targeting TrxR1 in NSCLC.
Main Methods:
- Synthesis of novel thioether derivatives based on a ROS-triggered prodrug strategy.
- Evaluation of prodrug cytotoxicity against NSCLC cells and ROS-triggered release rates.
- Investigation of the mechanism of action, including covalent binding to TrxR1 and its impact on enzyme activity.
- Assessment of antitumor efficiency in preclinical models, including nude mice and NSCLC organoids.
Main Results:
- Prodrug 5u demonstrated potent cytotoxicity against NSCLC cells and favorable ROS-triggered release kinetics.
- The active compound 6a, released from 5u, covalently binds to Cys475 and Sec498 residues of TrxR1, inhibiting its activity.
- Inhibition of TrxR1 led to redox homeostasis disruption, inducing apoptosis and ferroptosis in cancer cells.
- Prodrug 5u exhibited significant antitumor efficacy in both nude mice and NSCLC organoid models.
Conclusions:
- ROS-triggered prodrug 5u is a novel TrxR1 inhibitor with significant potential for NSCLC treatment.
- The developed prodrug strategy offers a promising approach for delivering covalent compounds to tumors via ROS activation.
- This research provides a new therapeutic avenue for NSCLC by targeting TrxR1 through a targeted prodrug delivery system.
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