PDTAC: Targeted Photodegradation of GPX4 Triggers Ferroptosis and Potent Antitumor Immunity

Liu, Sijin; Zhao, Xi; Shui, Sufang; Wang, Biao; Cui, Yingxian; Dong, Shuang; Kay, Lewis E.; Liu, G.

doi:10.1021/acs.jmedchem.2c00855

Cited by 31 publications

(21 citation statements)

References 39 publications

(63 reference statements)

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“…ARE-PROTAC could lead to a decrease in GSH levels and an increase in ROS levels in NSCLC cells. Ferroptosis is caused by the redox state disorder of the intracellular microenvironment, which is closely related to Nrf2. − The inhibition of Nrf2 function may be a potential strategy to enhance the sensitivity of NSCLC cells to ferroptosis. − Glutathione peroxidase 4 (GPX4), the key enzyme regulating ferroptosis, is the identified Nrf2 target gene. − To further investigate the influence of ARE-PROTACs on the ferroptosis process, the GPX4 levels were first evaluated. Compared to the vehicle control, C2 could reduce the mRNA and protein levels of GPX4 in a dose-dependent manner in NSCLC cells (Figure A,B).…”

Section: Resultsmentioning

confidence: 99%

ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer

Zhu

et al. 2023

J. Med. Chem.

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Proteolysis-targeting chimera (PROTAC) technology has emerged as a potential strategy to degrade "undruggable" proteins in recent years. Nrf2, an aberrantly activated transcription factor in cancer, is generally considered undruggable as lacking active sites or allosteric pockets. Here, we constructed the chimeric molecule C2, which consists of an Nrf2-binding element and a CRBN ligand, as a first-in-class Nrf2 degrader. Surprisingly, C2 was found to selectively degrade an Nrf2−MafG heterodimer simultaneously via the ubiquitin−proteasome system. C2 impeded Nrf2-ARE transcriptional activity significantly and improved the sensitivity of NSCLC cells to ferroptosis and therapeutic drugs. The degradation character of ARE-PROTACs suggests that the PROTAC hijacking the transcription element of TFs could achieve co-degradation of the transcription complex.

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Section: Resultsmentioning

confidence: 99%

ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer

Zhu

et al. 2023

J. Med. Chem.

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“…[58] For instance, selective degradation and antibody-drug conjugates can address disadvantages of low selectivity and poor PK properties of most GPX4 inhibitors. [59,60] Erastin's disadvantages of poor water solubility and unstable metabolism can be overcome by modifying its aniline ring. [58,61] In addition, small-molecule drugs that have been approved for ferroptosis in combination with each other or with other anti-cancer drugs is also a key point for small molecule drugs optimization.…”

Section: Small Molecule Drugs Hit a Bottleneckmentioning

confidence: 99%

Ferroptosis: The Entanglement between Traditional Drugs and Nanodrugs in Tumor Therapy

Liu

Huang

et al. 2023

Adv Healthcare Materials

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Ferroptosis is a non‐apoptotic programmed cell death caused by the accumulation of lipid peroxide. System Xc‐/glutathione peroxidase 4 (GPX4) axis and iron axis are two main pathways regulating ferroptosis. Simultaneously, multiple pathways are also involved in the ferroptosis regulation. Ferroptosis is an intense area of the current study. With the improvement of the regulatory mechanisms that underlie ferroptosis, a variety of drugs associated with ferroptosis have been discovered and developed for cancer therapy. Among them, traditional drugs were developed initially. Small molecule compounds that regulate ferroptosis signaling pathway and iron complexes that promote the Fenton reaction have become important drugs for inducing ferroptosis. In recent years, the emerging development of nanotechnology has promoted the research of ferroptosis nanodrugs. Iron‐based nanomaterials are extensively tested as ferroptosis‐inducing agents. Furthermore, nanoscale drug delivery systems offer a suitable scaffold for traditional drug therapies. Traditional drugs and nanodrugs are complementary, each with their own strengths and limitations. This review describes the latest studies on the regulation of ferroptosis in tumor cells and focuses on the entanglement between traditional drugs and nanodrugs. To conclude, the challenges and perspectives in this field are put forward.

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“…In another work, a small molecular probe PDTAC was designed to anchor ferroptosis‐related key enzyme GPX4 through covalently binding clinically approved PS verteporfin with GPX4‐targeting peptide (Figure 6F). [ 74 ] This probe can specifically degrade intracellular GPX4 protein through PDT, which can further induce obvious lipid peroxidation and ferroptosis in various tumor cells (Figure 6G). More importantly, such ferroptotic tumor cell death can elicit enough ICD‐related immunogenicity, including HMGB1 and ATP, which was demonstrated to stimulate DCs maturation in vitro while trigger strong antitumor immunity for inhibiting tumor growth in “gold standard” in vivo assessment of ICD (Figure 6H,I).…”

Section: Recent Design and Application Of Proinflammatory Rcd‐inducin...mentioning

confidence: 99%

mentioning

confidence: 99%

Recent Organic Photosensitizer Designs for Evoking Proinflammatory Regulated Cell Death in Antitumor Immunotherapy

Sun

Wang

et al. 2023

Small Methods

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In the past decades, immunotherapy has achieved a series of clinical successes in the field of cancer. However, existing therapeutic options usually show a low immune response to solid tumors caused by immunosuppressive “cold” tumor microenvironment (TME). Several types of proinflammatory regulated cell death (RCD), mainly including ferroptosis and pyroptosis, have been studied recently, which can provide proinflammatory signals and immunogenicity necessary for remodeling TME and activating an antitumor immune response. A variety of chemotherapeutic drugs are proven to be effective in the proinflammatory RCD induction of tumor cells, but several adverse effects and intrinsic drug resistance usually occur in the therapeutic process, greatly hindering their further clinical application. The emerging organic photosensitizer (PS)‐based materials open new possibilities to effectively activate proinflammatory RCD through precise spatiotemporal regulation of intracellular reactive oxygen species‐associated signaling pathways, which can overcome many challenges encountered in current proinflammatory RCD‐mediated immunotherapy. In this review, the recent design strategies of PS probes are detailly summarized and their potential advantages for tumor‐specific proinflammatory RCD induction are discussed. Moreover, the representative examples in cancer immunotherapy are highlighted and future perspectives in this emerging field are proposed.

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PDTAC: Targeted Photodegradation of GPX4 Triggers Ferroptosis and Potent Antitumor Immunity

Cited by 31 publications

References 39 publications

ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer

ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer

Ferroptosis: The Entanglement between Traditional Drugs and Nanodrugs in Tumor Therapy

Recent Organic Photosensitizer Designs for Evoking Proinflammatory Regulated Cell Death in Antitumor Immunotherapy

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