Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics

Li, Qingke; Qu, Chen; Klauser, Paul C.; Li, Mengyuan; Zheng, Feng; Wang, Nanxi; Li, Xiaoying; Zhang, Qianbing; Fu, Xuemei; Wang, Qian; Xu, Yang; Wang, Lei

doi:10.1016/j.cell.2020.05.028

Cited by 147 publications

(168 citation statements)

References 58 publications

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“…Numerous antitumor agents have been reported to increase ROS production in cancer cells . Different mechanisms have been studied, such as redox cycling and mitochondrial oxidase activation . Our results indicated that the most active gold(I) complex 4 b containing an OA derivative targets TrxR to induce ROS in A2780 cells and activate ROS‐dependent ERS activation.…”

Section: Resultsmentioning

confidence: 82%

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Bian

Sun

Liu

et al. 2020

Chemistry A European J

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Many cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to furthero xidative impairment triggered by agentsg enerating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be ap romising anticancer strategy.H erein, it is shown that ag old(I) complex containing an oleanolic acid derivative (4b)i nduces apopto-sis of ovarian cancerA 2780 cells by activatinge ndoplasmic reticulum stress (ERS). It can inhibitT rxR enzymea ctivity to elevateR OS, mediate ERS and mitochondriald ysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably,t his complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.[a] Dr.[ + + ] These authors contributed equally to this work.[**] ERS:e ndoplasmic reticulums tress, ROS:r eactive oxygen species, TrxR:t hioredoxin reductase.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

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Section: Resultsmentioning

confidence: 82%

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Bian

Sun

Liu

et al. 2020

Chemistry A European J

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“…Herein, we report the covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency. Relying on the recently developed proximity enabled covalent binding reaction [12][13][14][15] , we created the covalently engineered nanobody chimeras that can irreversibly bind to membrane protein targets via proximity-enabled crosslinking, while the conjugated CPP and LSS allowed the lysosomemediated target degradation (Fig. 1A).…”

Section: Main Textmentioning

confidence: 99%

Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation

et al. 2021

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The targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current proteolysis-targeting chimera (PROTAC) methodology. We herein report a covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency. We first established a mass-spectrometry-based screening platform for the rapid development of a covalent nanobody (GlueBody) that allowed proximity-enabled cross-linking with surface antigens on cancer cells. By conjugation with a cell-penetrating peptide and a lysosomal-sorting sequence, the resulting GlueTAC chimera triggered the internalization and degradation of programmed death-ligand 1 (PD-L1), which provides a new avenue to target and degrade cell-surface proteins.

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“…Moreover, PDXs based on immunocompromised mice are limited in experiments of immunomodulatory compounds ( Chen and Mellman, 2017 ). Alternatively, the humanized mice, generated through transplantation of human immune cells or hematopoietic stem cells into immune-deficient mice, could reconstitute the human immunologic environment, although with challenging technique concerns ( Buque and Galluzzi, 2018 ; Li et al, 2020 ).…”

Section: Current Human-derived Models In Ocmentioning

confidence: 99%

Application of Ovarian Cancer Organoids in Precision Medicine: Key Challenges and Current Opportunities

Yang

Huang

Cheng

et al. 2021

Front. Cell Dev. Biol.

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Ovarian cancer (OC) is the leading cause of death among gynecologic malignances. Over the past decades, human-derived models have advanced from monolayer cell cultures to three-dimensional (3D) organoids that could faithfully recapitulate biological characteristics and tumor heterogeneity of primary tissues. As a complement of previous studies based on cell lines or xenografts, organoids provide a 3D platform for mutation–carcinogenesis modeling, high-throughput drug screening, genetic engineering, and biobanking, which might fulfill the gap between basic research and clinical practice. Stepwise, cutting-edge bioengineering techniques of organoid-on-a-chip and 3D bioprinting might converge current challenges and contribute to personalized therapy. We comprehensively reviewed the advantages, challenges, and translational potential of OC organoids. Undeniably, organoids represent an excellent near-physiological platform for OC, paving the way for precision medicine implementation. Future efforts will doubtlessly bring this innovative technique from bench to bedside.

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Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics

Cited by 147 publications

References 58 publications

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation

Application of Ovarian Cancer Organoids in Precision Medicine: Key Challenges and Current Opportunities

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