Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Salama, Abdelrahman K A A; Trkulja, Marija V; Casanova, Emilio; Uras, Iris Z.

doi:10.3390/ijms232315440

Cited by 11 publications

(4 citation statements)

References 219 publications

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“…Among the PROTACs discovered so far, 20 of them are currently undergoing clinical trials for anticancer treatment ( Table 1 ) [ 26 , 29 , 30 , 31 ]. They respectively target and degrade 11 different oncogenic proteins by recruiting two other types of E3 ligases, cereblon (CRBN) and von Hippel-Lindau (VHL) E3 ligases.…”

Section: Protac For Anticancer Therapymentioning

confidence: 99%

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

et al. 2023

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Proteolysis-targeting chimeras (PROTACs) are rapidly emerging as a potential therapeutic strategy for cancer therapy by inducing the degradation of tumor-overexpressing oncogenic proteins. They can specifically catalyze the degradation of target oncogenic proteins by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway. Since their mode of action is universal, irreversible, recyclable, long-lasting, and applicable to ‘undruggable’ proteins, PROTACs are gradually replacing the role of conventional small molecular inhibitors. Moreover, their application areas are being expanded to cancer immunotherapy as various types of oncogenic proteins that are involved in immunosuppressive tumor microenvironments. However, poor water solubility and low cell permeability considerably restrict the pharmacokinetic (PK) property, which necessitates the use of appropriate delivery systems for cancer immunotherapy. In this review, the general characteristics, developmental status, and PK of PROTACs are first briefly covered. Next, recent studies on the application of various types of passive or active targeting delivery systems for PROTACs are introduced, and their effects on the PK and tumor-targeting ability of PROTACs are described. Finally, recent drug delivery systems of PROTACs for cancer immunotherapy are summarized. The adoption of an adequate delivery system for PROTAC is expected to accelerate the clinical translation of PROTACs, as well as improve its efficacy for cancer therapy.

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Section: Protac For Anticancer Therapymentioning

confidence: 99%

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

et al. 2023

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“…In particular, the last represents a rapidly exploding drug discovery strategy that mainly uses two classes of small molecules, the proteolysis targeting chimeras (PROTACs) or molecular glues, which mediate TF targeted protein degradation via the ubiquitin - proteasome pathway through distinct mechanisms. Several PROTACs-based TF-targeting platforms have been developed as a tool to advance drugging TFs and a number of PROTACs targeting TFs, including STAT3, are currently undergoing clinical trials [ 115 ].…”

Section: Tfs In Cafs As Clinical Potential Therapeutic Targetsmentioning

confidence: 99%

Transcription factors in fibroblast plasticity and CAF heterogeneity

Melchionna,

Trono,

Di Carlo

et al. 2023

J Exp Clin Cancer Res

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In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings.The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways. Recent advances in single-cell RNA sequencing technology have emphasized the role of transcription factors in the conversion of normal fibroblasts to distinct CAF subtypes across various cancer types.This review provides a comprehensive overview of the specific roles of transcription factor networks in shaping CAF heterogeneity, plasticity, and functionality. Beginning with their influence on fibroblast homeostasis and reprogramming during wound healing and fibrosis, it delves into the emerging insights into transcription factor regulatory networks. Understanding these mechanisms not only enables a more precise characterization of CAF subsets but also sheds light on the early regulatory processes governing CAF heterogeneity and functionality. Ultimately, this knowledge may unveil novel therapeutic targets for cancer treatment, addressing the existing challenges of stromal-targeted therapies.

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“…Advances in chemical biology have made it possible to use the proteasomal and endo‐lysosomal protein degradation pathways to rapidly destabilize soluble intra‐ and extracellular proteins, as well as membrane proteins with dose tunability, reversibility, and high selectivity (Fig. 1 ) [ 110 , 111 , 112 , 113 ]. Since the array of systems and technologies developed is vast and ever‐expanding, we provide a general conceptual framework and highlight systems that can be easily implemented in a laboratory setting, using off‐the‐shelf reagents, without the need for screening protein binders and synthesizing novel compounds.…”

Section: Targeted Protein Degradation ( Tpd ) For ...mentioning

confidence: 99%

Genetic manipulation and targeted protein degradation in mammalian systems: practical considerations, tips and tricks for discovery research

Giandomenico

Schuman

2023

FEBS Open Bio

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Gaining a mechanistic understanding of the molecular pathways underpinning cellular and organismal physiology invariably relies on the perturbation of an experimental system to infer causality. This can be achieved either by genetic manipulation or by pharmacological treatment. Generally, the former approach is applicable to a wider range of targets, is more precise, and can address more nuanced functional aspects. Despite such apparent advantages, genetic manipulation (i.e., knock‐down, knock‐out, mutation, and tagging) in mammalian systems can be challenging due to problems with delivery, low rates of homologous recombination, and epigenetic silencing. The advent of CRISPR‐Cas9 in combination with the development of robust differentiation protocols that can efficiently generate a variety of different cell types in vitro has accelerated our ability to probe gene function in a more physiological setting. Often, the main obstacle in this path of enquiry is to achieve the desired genetic modification. In this short review, we will focus on gene perturbation in mammalian cells and how editing and differentiation of pluripotent stem cells can complement more traditional approaches. Additionally, we introduce novel targeted protein degradation approaches as an alternative to DNA/RNA‐based manipulation. Our aim is to present a broad overview of recent approaches and in vitro systems to study mammalian cell biology. Due to space limitations, we limit ourselves to providing the inexperienced reader with a conceptual framework on how to use these tools, and for more in‐depth information, we will provide specific references throughout.

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Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Cited by 11 publications

References 219 publications

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

Transcription factors in fibroblast plasticity and CAF heterogeneity

Genetic manipulation and targeted protein degradation in mammalian systems: practical considerations, tips and tricks for discovery research

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