Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells

Wang, Han; Wang, Chao; Li, Bingru; Zheng, Cangxin; Liu, Guoquan; Liu, Zhenming; Zhang, Liangren; Xu, Ping

doi:10.1016/j.ejmech.2023.115343

Cited by 17 publications

(7 citation statements)

References 34 publications

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“…Han Wang et al synthesized a series of GPX4 PROTACs utilizing ML210 as the binding ligand for GPX4, CRBN as the E3 ligase-binding ligand, and various lengths of piperazine rings as linkers. 226 Among these, DC-2 exhibited the most potent degradation activity in HT1080 cells, with a DC 50 value of 0.03 μM and a significant inhibitory effect on HT1080 cells, with an IC 50 value of 0.1 μM. DC-2 not only triggers GPX4 degradation through the ubiquitin-proteasome pathway and the autophagy-lysosomal pathway but also induces the formation of GPX4 mitochondrial isoforms.…”

Section: Ferroptosis Inducersmentioning

confidence: 93%

“…DC-2 not only triggers GPX4 degradation through the ubiquitin-proteasome pathway and the autophagy-lysosomal pathway but also induces the formation of GPX4 mitochondrial isoforms. 226 DC-2 outperformed ML210 by degrading GPX4 22-fold more and demonstrated equivalent or superior antiproliferative activity against HT1080, Calu-1, and A375 cells compared to ML210. Additionally, DC-2 exhibited better tumor cell selectivity and safety.…”

Section: Ferroptosis Inducersmentioning

confidence: 98%

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Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Luo,

Bai,

Zhang

et al. 2024

DDDT

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Section: Ferroptosis Inducersmentioning

confidence: 93%

Section: Ferroptosis Inducersmentioning

confidence: 98%

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Luo,

Bai,

Zhang

et al. 2024

DDDT

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“…Treatment with erastin, sorafenib or sulfasalazine effectively inhibits the activity of SLC7A11, leading to the depletion of intracellular GSH, which leads to the inactivation of GPX4 and induces ferroptosis in tumor cells [ 139 , 140 , 141 ]. Additionally, blocking GPX4 signaling with RSL3 or ML210 and promoting GPX4 degradation with FIN56 or PdPT induces ferroptosis [ 142 , 143 , 144 , 145 ]. Moreover, buthionine sulfoximine (BSO) promotes ferroptosis by inhibiting γ‐glutamylcysteine synthase (γ‐GCS), the rate‐limiting enzyme in GSH synthesis, thereby reducing the level of reduced GSH and the activity of GPX4 [ 140 ].…”

Section: Ferroptosis Inducersmentioning

confidence: 99%

Cellular metabolism: A key player in cancer ferroptosis

Jiang,

Peng,

Peng

et al. 2024

Cancer Communications

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Cellular metabolism is the fundamental process by which cells maintain growth and self‐renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron‐dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron‐induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.

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“…Tian et al [ 195 ] connected Hb to Ce6 to load sorafenib (SRF, an iron death promoter) and built a nanoplatform SRF@Hb-Ce6. Hb not only provides O 2 and increases PDT efficacy, but it also synergizes with SPF, significantly increases the generation of lipid peroxides, downregulates GPX4 expression, and increases tumor cell iron death [ 196 ]. This platform shows promise as a nanoplatform for combination cancer therapy.…”

Section: Nano-hbocs For Cancer Therapymentioning

confidence: 99%

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

Zhu,

Wang,

Xiao

et al. 2024

J Nanobiotechnol

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Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases. Graphical Abstract

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Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells

Cited by 17 publications

References 34 publications

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Cellular metabolism: A key player in cancer ferroptosis

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

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