Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Xiao, Zhangping; Song, Shanshan; Chen, Deng; Merkerk, Ronald van; Wouden, Petra E van der; Cool, Robbert H.; Quax, Wim J.; Poelarends, Gerrit J.; Melgert, Barbro N.

doi:10.1002/ange.202101864

Cited by 5 publications

(3 citation statements)

References 64 publications

(80 reference statements)

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“…c) Western blot assay of GPX4 level in HT‐1080 cells treated with different concentrations of ML162 and pomalidomide. d) Rescue from dGPX4‐mediated GPX4 degradation upon co‐treatment with CRBN‐inhibitor, pomalidomide, [16] and MG‐132. HT‐1080 cells were pre‐treated with indicated compounds for 12 h.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

et al. 2022

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Ferroptosis is a new form of regulated, nonapoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (

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Section: Resultsmentioning

confidence: 99%

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

et al. 2022

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“…Nuclear focal adhesion kinase (FAK) is overexpressed in various tumours, including lung cancer (179). The Fak-targeted PROTAC GSK215 can significantly inhibit the migration of A549 cells, and induce rapid and long-term degradation of FAK, with lasting effects on FAK levels (180).…”

Section: The Roles Of Protacs In Other Targets Associated With Nsclcmentioning

confidence: 99%

Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer

Yang

Zhao²,

Jin³

et al. 2023

Front. Oncol.

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Lung cancer is one of the most common malignant tumours worldwide, with the highest mortality rate. Approximately 1.6 million deaths owing to lung cancer are reported annually; of which, 85% of deaths occur owing to non-small-cell lung cancer (NSCLC). At present, the conventional treatment methods for NSCLC include radiotherapy, chemotherapy, targeted therapy and surgery. However, drug resistance and tumour invasion or metastasis often lead to treatment failure. The ubiquitin–proteasome pathway (UPP) plays an important role in the occurrence and development of tumours. Upregulation or inhibition of proteins or enzymes involved in UPP can promote or inhibit the occurrence and development of tumours, respectively. As regulators of UPP, ubiquitin-specific proteases (USPs) primarily inhibit the degradation of target proteins by proteasomes through deubiquitination and hence play a carcinogenic or anticancer role. This review focuses on the role of USPs in the occurrence and development of NSCLC and the potential of corresponding targeted drugs, PROTACs and small-molecule inhibitors in the treatment of NSCLC.

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“…[19][20][21][22][23] As a result, a fast growing number of protein targets have been extensively documented to be degraded by PROTACs. [24][25][26][27][28][29][30] Despite substantial progress, there are still several issues that need to be addressed before its clinical translation is realized. 31 Firstly, the majority of these systems are limited to small molecule-based PROTACs, which cannot locate more precisely at the target tumor tissue and thus often suffer from the off-target effects.…”

Section: Introductionmentioning

confidence: 99%

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

Liu

Chen

et al. 2022

Preprint

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Nucleocytoplasmic shuttling proteins (NSPs) has emerged as a promising class of therapeutic targets for many diseases including cancer. However, most reported NSPs-based therapies largely rely on small molecule inhibitors with limited efficacy and off-target effects. Proteolysis targeting chimera (PROTAC) represents a revolutionary inhibitory modality for targeted protein degradation with many advantages, including substoichiometric catalytic activity, improved selectivity, and high efficacy. However, the majority of reported PROTACs so far are still limited to the degradation of cytoplasmic proteins and lack of tumor-specific targeting. To realize the full potential of the PROTAC technology and broaden its applications for the degradation of NSPs, we herein report a conceptual approach for the design of a new archetype of PROTAC (denoted as PS-ApTCs) by introducing phosphorothioate-modified AS1411 aptamer to a ligand of the CRBN E3 ligase, realizing tumor-targeting and spatioselective degradation with improved efficacy. We have demonstrated that PS-ApTCs is capable of effectively degrading nucleolin in target cell membrane and cytoplasm but not in the nucleus, in a CRBN- and proteasome-dependent manner. In addition, PS-ApTCs exhibits superior antiproliferation, pro-apoptotic, and cell cycle arrest potencies. Importantly, we demonstrate for the first time that combination of PS-ApTCs-mediated nucleolin degradation with aptamer-drug conjugates-based chemotherapy can enable an AND-gated synergistic effect on tumor inhibition. Collectively, our results suggest that PS-ApTCs possess the ability to expand the PROTACs toolbox to even wider range of targets in subcellular localization and accelerate the discovery of new combinational therapeutic approaches.

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Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Cited by 5 publications

References 64 publications

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer

Cooperatively Designed Aptamer-PROTACs for Spatioselective Degradation of Nucleocytoplasmic Shuttling Protein for Enhanced Combinational Therapy

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