Light-induced control of protein destruction by opto-PROTAC

Liu, Jing; Chen, He; Ma, Leina; He, Zhixiang; Wang, Dong; Liu, Yi; Lin, Qian; Zhang, Tinghu; Gray, Nathanael S.; Kanıskan, H. Ümit; Jin, Jian; Wei, Wenyi

doi:10.1126/sciadv.aay5154

Cited by 158 publications

(191 citation statements)

References 52 publications

(85 reference statements)

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“…Indeed, the tissuespecific expression of E3 ligases used in PROTACs will need to be ascertained as well as the impact that drafting an endogenous E3 ligase for therapeutic help might have on the system. Further exciting developments include combining optogenetics with protein degrader strategies such as Opto-PROTACs, as this could provide added control over the timing and induction of protein degradation (424).…”

Section: Discussionmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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“… 264 Specifically, PROTAC consists two functional parts, connected by a chemical linker: a “warhead” (normally a small molecule) that binds to a targeted protein, and a ligand which is recognized by a cullin-RING ligase, leading to degradation of the target protein. 264 As such, PROTAC provides an effective approach to target these undruggable proteins, 265 – 267 such as transcriptional factor SOX2 (Fig. 7 , approach 7).…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

“…Given its fundamental role in embryonic development 3 and epithelial tissue homeostasis, 188 associated cytotoxicity of SOX2 targeting should be an important issue to consider. A newly developed light-inducible switch on PROTAC, which triggers the degradation of any given targeted proteins restrictedly at desirable site and time window by ultraviolet irradiation, 267 , 268 should be incorporated in the SOX2-targeting strategy of PROTAC to overcome the potential side-effects.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Functional characterization of SOX2 as an anticancer target

Zhang

Xiong

Sun

2020

Sig Transduct Target Ther

111

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SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and posttranslation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/ metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.

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“…In light-controllable PROTACs, a photo-removable group is attached to either a POI ligand or E3 ligand or linker. This photo-removable group is detached from the PROTAC upon light irradiation converting it to an active PROTAC [ 23 , 30 , 31 ]. The design and mechanisms of action of homo-PROTACs and light-controllable PROTACs are illustrated in Fig.…”

Section: Advantages Of Using Protacs Over Other Approaches To Inhibitmentioning

confidence: 99%

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

Khan

Huo

et al. 2020

J Hematol Oncol

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a substoichiometric manner), ability to target "undruggable" and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/ selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.

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Light-induced control of protein destruction by opto-PROTAC

Cited by 158 publications

References 52 publications

Targeting the Ubiquitin System in Glioblastoma

Targeting the Ubiquitin System in Glioblastoma

Functional characterization of SOX2 as an anticancer target

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

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