Targeted Degradation of PD‐L1 and Activation of the STING Pathway by Carbon‐Dot‐Based PROTACs for Cancer Immunotherapy

Su, Wen; Tan, Mixiao; Wang, Zhihang; Zhang, Jie; Huang, Wenping; Song, Haohao; Wang, Xingye; Ran, Haitao; Gao, Yanfeng; Nie, Guangjun; Wang, Hai

doi:10.1002/anie.202218128

Cited by 41 publications

(38 citation statements)

References 37 publications

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“…By depleting HER2, GNCTACs efficiently inhibited the growth of SKBR3 tumors with FMD treatment. Since the ubiquitination system is distributed in the cytoplasm, membrane proteins are not considered ideal targets for PROTACs. − Our results showed that GNCTACs could be used for membrane protein degradation with high efficiency.…”

Section: Introductionmentioning

confidence: 91%

Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

Wang

Tan

et al. 2023

J. Med. Chem.

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Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein–protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.

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Section: Introductionmentioning

confidence: 91%

Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

Wang

Tan

et al. 2023

J. Med. Chem.

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“…At present, VHL E3 ligand has been widely and successfully applied in the design and synthesis of PROTAC as one of the most commonly used E3 ligands (Table 1). 13,17,18,142–154 …”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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“…Carbon-dots, a new carbon-based quasi-spherical nanomaterial with diameters below 10 nm, good biocompatibility and photoluminescence, have been conjugated with PD-L1 and E3 ligase targeting probes [24]. After injection into tumor-bearing animals, caloric restriction enhanced the uptake of these modified carbon-dots by PD-L1-expressing cells resulting in increased proteasome activity and almost complete PD-L1 ubiquitination and degradation, followed by activation of dendritic and cytotoxic T cells and inhibition of tumor growth without evident systemic toxicity [24].…”

Section: Effects Of Caloric Restriction In Preclinical Cancer Modelsmentioning

confidence: 99%

Caloric restriction and fasting-mimicking diets in the treatment of cancer patients

Arends

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of review Different forms of caloric restriction for patients with cancer are widely advertised in lay circles, based mainly on promising preclinical experiments, while evidence from clinical trials is still preliminary. This review aims to present physiological responses to fasting and update knowledge on recently accumulated evidence from preclinical models and clinical trials. Recent findings Like other mild stressors, caloric restriction induces hormetic changes in healthy cells, which increase the tolerance to subsequent more severe stressors. While protecting healthy tissues, caloric restriction sensitizes malignant cells to toxic interventions because of their deficiencies in hormetic mechanisms, especially control of autophagy. In addition, caloric restriction may activate anticancer-directed immune cells and deactivate suppressive cells, thus increasing immunosurveillance and anticancer cytotoxicity. These effects may combine to increase the effectivity of cancer treatments while limiting adverse events. Though evidence obtained from preclinical models is promising, clinical trials in cancer patients so far have been preliminary. In clinical trials it will remain essential to avoid inducing or aggravating malnutrition. Summary Based on physiology and evidence from preclinical models, caloric restriction is a promising candidate as a potential combination partner for clinical anticancer treatment. However, large randomized clinical trials investigating effects on clinical outcome in patients with cancer are still lacking.

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Targeted Degradation of PD‐L1 and Activation of the STING Pathway by Carbon‐Dot‐Based PROTACs for Cancer Immunotherapy

Cited by 41 publications

References 37 publications

Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

PROTACs: A novel strategy for cancer drug discovery and development

Caloric restriction and fasting-mimicking diets in the treatment of cancer patients

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