Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs

Gong, Linghui; Cui, Di; Xiong, Xiufang; Zhao, Yongchao

doi:10.1007/978-981-15-1025-0_19

Cited by 10 publications

(6 citation statements)

References 146 publications

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“…The RING-type E3 ligase inhibitors developed in recent years are mainly small-molecule inhibitors targeting CRLs [ 173 , 203 ]. CRLs composed of Cullin family proteins, RING proteins, linker proteins, and substrate recognition subunits are the largest family of E3 ligases that can regulate the degradation of many proteins with different functions and structures.…”

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

“…Disrupting the VHL/HIF-α interaction may affect the HIF-independent tumor suppressor function of pVHL. The small-molecule inhibitors currently developed for p-VHL/HIF-1α include compound 15, compound 7, and VH298 [ 173 , 174 ]. However, the specific mechanism through which these small-molecule inhibitors affect cancer immunotherapy remains unclear.…”

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

“…It plays a crucial role in cancer development and progression. It is overexpressed in various human cancers [ 215 ] and is associated with poor cancer prognosis [ 7 , 173 ]. The SCF Skp2 complex performs its carcinogenic function by promoting the ubiquitination of substrates such as p27, FOXO1, p21, and p57 and subsequent proteasome degradation [ 181 ].…”

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

“…Among the developed selective small molecular inhibitors of Skp2, mechanisms through which different inhibitors exert their antitumor effects by inhibiting the activity of the Skp2 E3 ligase are different [ 173 , 215 ]. For example, Compound A blocks the assembly of Skp2 in the SCF complex [ 175 ]; C1, C2, C16, and C20 inhibit p27 ubiquitination by targeting the binding interface between Skp2–Cks1 and p27 [ 176 ]; Compound 25 inhibits the formation of the Skp2–Skp1 complex [ 177 ]; DT204 reduces Skp2 binding to Cullin-1 and Commd1 (Cullin-1 binding protein) [ 178 ]; and betulinic acid binds to Skp2, reducing its stability and the accumulation of its substrate protein [ 179 ].…”

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

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Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Chi

Cha

et al. 2021

Cells

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Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.

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Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

See 2 more Smart Citations

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Chi

Cha

et al. 2021

Cells

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“…NEDD8 bound to Cullin proteins also prevents the binding of Cullin-associated and NEDDylation-dissociated protein 1 (CAND1) [22], a protein which facilitates the exchange of substrate receptors from the CRL (reviewed in [23]). For a more detailed description of canonical NEDD8-Cullin interactions, the reader is encouraged to consult a compilation of recently published, in-depth review articles [15,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. The remainder of this article will focus instead on instances where NEDD8 modification has been detected on other proteins and what function this may have in the cell (see Figure 1 for a summary of canonical and non-canonical NEDD8 substrates).…”

Section: Nedd8 Modification Of Cullinsmentioning

confidence: 99%

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

Vijayasimha

Dolan

2021

Cells

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Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) is a ubiquitin-like protein (UBL) whose canonical function involves binding to, and thus, activating Cullin–Ring finger Ligases (CRLs), one of the largest family of ubiquitin ligases in the eukaryotic cell. However, in recent years, several non-canonical protein substrates of NEDD8 have been identified. Here we attempt to review the recent literature regarding non-canonical NEDDylation of substrates with a particular focus on how the covalent modification of NEDD8 alters the protein substrate. Like much in the study of ubiquitin and UBLs, there are no clear and all-encompassing explanations to satisfy the textbooks. In some instances, NEDD8 modification appears to alter the substrates localization, particularly during times of stress. NEDDylation may also have conflicting impacts upon a protein’s stability: some reports indicate NEDDylation may protect against degradation whereas others show NEDDylation can promote degradation. We also examine how many of the in vitro studies measuring non-canonical NEDDylation were conducted and compare those conditions to those which may occur in vivo, such as cancer progression. It is likely that the conditions used to study non-canonical NEDDylation are similar to some types of cancers, such as glioblastoma, colon and rectal cancers, and lung adenocarcinomas. Although the full outcomes of non-canonical NEDDylation remain unknown, our review of the literature suggests that researchers keep an open mind to the situations where this modification occurs and determine the functional impacts of NEDD8-modification to the specific substrates which they study.

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The mechanism of action and clinical value of PROTACs: A graphical review

Graham

2022

Cellular Signalling

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Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs

Cited by 10 publications

References 146 publications

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation

The mechanism of action and clinical value of PROTACs: A graphical review

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