Recent advances in targeted protein degraders as potential therapeutic agents

Yang, Na; Kong, Bo; Zhu, Zhaohong; Huang, Fei; Li-liang, Zhang; Lü, Tao; Chen, Yadong; Zhang, Yanmin; Jiang, Yulei

doi:10.1007/s11030-023-10606-w

Cited by 12 publications

(7 citation statements)

References 101 publications

(192 reference statements)

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“…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][34][35] PROTACs have been shown to be able to overcome some of the disadvantages of conventional therapies, with very promising results, both in vitro and in vivo. [36][37][38] In such a way that they have progressed through various stages of preclinical and clinical development for the treatment of several types of diseases, with a special focus on cancer treatment.…”

Section: 29mentioning

confidence: 99%

“…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 , 34 , 35…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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Section: 29mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Vicente,

Salvador

2024

MedComm

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“…The N-terminal oligomerization area and the C-terminal instability region of PROTAC molecules were joined by fusion of the X-N-proteins and C-terminal unstable sections, resulting in the formation of two distinct types of PROTAC molecules. Additionally, they were able to create several fusion peptides by replacing the C-terminal dangerous region with the oxygen-structured degradation (ODD) region of hypoxia-inducible factor (HIF-1), which interacts with VHL-type E3 ligase [ 93 ]. Due to the previous ligand, they had been equally effective at destroying PROTAC, proving that the C-terminal’s dangerous area can also be utilized as an E3 ligase ligand.…”

Section: Protacs: Targeted Management Strategy For Several Diseased C...mentioning

confidence: 99%

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Sincere,

Anand,

Ashique

et al. 2023

Molecules

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A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using the PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits protein function for a short period of time to temporarily alter it. By utilizing an event-driven MOA, the proteolysis-targeting chimeras (PROTACs) technology introduces a revolutionary tactic. Small-molecule-based heterobifunctional PROTACs hijack the ubiquitin–proteasome system to trigger the degradation of the target protein. The main challenge PROTAC’s development facing now is to find potent, tissue- and cell-specific PROTAC compounds with favorable drug-likeness and standard safety measures. The ways to increase the efficacy and selectivity of PROTACs are the main focus of this review. In this review, we have highlighted the most important discoveries related to the degradation of proteins by PROTACs, new targeted approaches to boost proteolysis’ effectiveness and development, and promising future directions in medicine.

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“…However, these challenges can be addressed by utilizing mRNA or dye used to localize the nucleus of cells (DNA) delivery systems. 1 One of their greatest advantages is their capability to target undruggable proteins, 13 so newer PROTAC designs will allow new molecules and targets to be developed.…”

Section: Introductionmentioning

confidence: 99%

mRNA PROTACs: engineering PROTACs for high‐efficiency targeted protein degradation

Xue,

Zhang,

et al. 2024

MedComm

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Proteolysis‐targeting chimeras (PROTACs) are essential bifunctional molecules that target proteins of interest (POIs) for degradation by cellular ubiquitination machinery. Despite significant progress made in understanding PROTACs' functions, their therapeutic potential remains largely untapped. As a result of the success of highly flexible, scalable, and low‐cost mRNA therapies, as well as the advantages of the first generation of peptide PROTACs (p‐PROTACs), we present for the first time an engineering mRNA PROTACs (m‐PROTACs) strategy. This design combines von Hippel–Lindau (VHL) recruiting peptide encoding mRNA and POI‐binding peptide encoding mRNA to form m‐PROTAC and promote cellular POI degradation. We then performed proof‐of‐concept experiments using two m‐PROTACs targeting two cancer‐related proteins, estrogen receptor alpha and B‐cell lymphoma‐extra large protein. Our results demonstrated that m‐PROTACs could successfully degrade the POIs in different cell lines and more effectively inhibit cell proliferation than the traditional p‐PROTACs. Moreover, the in vivo experiment demonstrated that m‐PROTAC led to significant tumor regression in the 4T1 mouse xenograft model. This finding highlights the enormous potential of m‐PROTAC as a promising approach for targeted protein degradation therapy.

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Recent advances in targeted protein degraders as potential therapeutic agents

Cited by 12 publications

References 101 publications

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

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

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

mRNA PROTACs: engineering PROTACs for high‐efficiency targeted protein degradation

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