PROTACs: A novel strategy for cancer drug discovery and development

Han, Xin; Sun, Yi

doi:10.1002/mco2.290

Cited by 14 publications

(3 citation statements)

References 427 publications

(862 reference statements)

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“…Thus, PROTACs exploit the ubiquitin-proteasome system to selectively eliminate specific proteins, opening new avenues for therapeutic interventions. A rise in PROTAC research has been seen mostly on cancer research [143,145], but it has also been explored for antiviral therapy. Based on this premise, it is possible to envision a strategy correlating PROTACs and known inhibitors.…”

Section: Targeted Protein Degradation Strategiesmentioning

confidence: 99%

Recent Advances on Targeting Proteases for Antiviral Development

Borges,

Ferreira,

Silva

2024

Viruses

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Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible for causing diseases in humans, like the West Nile virus (WNV) and the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the mechanisms behind blocking viral protease’s function is pivotal for the development of new antiviral drugs and therapeutical strategies. Apart from directly inhibiting the target protease, usually by targeting its active site, several new pathways have been explored to impair its activity, such as inducing protein aggregation, targeting allosteric sites or by inducing protein degradation by cellular proteasomes, which can be extremely valuable when considering the emerging drug-resistant strains. In this review, we aim to discuss the recent advances on a broad range of viral proteases inhibitors, therapies and molecular approaches for protein inactivation or degradation, giving an insight on different possible strategies against this important class of antiviral target.

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Section: Targeted Protein Degradation Strategiesmentioning

confidence: 99%

Recent Advances on Targeting Proteases for Antiviral Development

Borges,

Ferreira,

Silva

2024

Viruses

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“…PROTACs are a class of molecules that allow direct protein knockdown via the proteasomal degradation pathway. While traditional targeted drugs require strong binding affinity for the target protein, agents such as PROTACs can label a target protein through weak binding, thus offering a potential solution for 80% of the “undruggable” targets [ 12 , 13 ]. PROTACs are hetero-bifunctional molecules that contain two ligands connected by a linker: one for recruitment and binding to the target protein, and the other for recruitment and binding to E3 ubiquitin ligase ( Figure 1 ).…”

Section: Protacsmentioning

confidence: 99%

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

Joshi,

Dey,

2023

Exploration of Targeted Anti-Tumor Therapy

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A generalized therapeutic strategy for various disease conditions, including cancer, is to deplete or inactivate harmful protein targets. Various forms of protein or gene silencing molecules, e.g., small molecule inhibitors, RNA interference (RNAi), and microRNAs (miRNAs) have been used against druggable targets. Over the past few years, targeted protein degradation (TPD) approaches have been developed for direct degradation of candidate proteins. Among the TPD approaches, proteolysis targeting chimeras (PROTACs) have emerged as one of the most promising approaches for the selective elimination of proteins via the ubiquitin-proteasome system. Other than PROTACs, TPD methods with potential therapeutic use include intrabody-mediated protein knockdown and tripartite motif-21 (TRIM-21) mediated TRIM-Away. In this review, protein knockdown approaches, their modes of action, and their advantages over conventional gene knockdown approaches are summarized. In cancers, disease-associated protein functions are often executed by specific post-translational modifications (PTMs). The role of TRIM-Away is highlighted in the direct knockdown of PTM forms of target proteins. Moreover, the application challenges and the prospective clinical use of TPD approaches in various diseases are also discussed.

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“…In order to overcome these difficulties, investigations have essentially focused on the development of new inhibitors, the research and study of new therapeutic targets, as well as the development of new therapeutic strategies. Among the novel therapeutic strategies that have emerged over the last few years, targeted protein degradation using bifunctional molecules known as PROteolysis‐TArgeting Chimeras (PROTACs) has demonstrated unprecedented results 33–35 …”

Section: Introductionmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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PROTACs: A novel strategy for cancer drug discovery and development

Cited by 14 publications

References 427 publications

Recent Advances on Targeting Proteases for Antiviral Development

Recent Advances on Targeting Proteases for Antiviral Development

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

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