Development of cell-permeable peptide-based PROTACs targeting estrogen receptor α

Dai, Yuxuan; Na, Yue; Gong, Junni; Liu, Chunxia; Li, Qifei; Zhou, Jiaqi; Huang, Wenlong; Qian, Hai

doi:10.1016/j.ejmech.2019.111967

Cited by 31 publications

(32 citation statements)

References 34 publications

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“…As an illustration, WBP2 sequence-derived peptides comprising the PY motifs and/or phosphorylation sites could be designed as competitive inhibitors against the functional Cterminus of WBP2 [69]. A key challenge in this approach is the effective delivery of the peptide into the cells, which could be circumvented by tagging a cell-permeable sequence to the therapeutic peptide [70]. Preliminary studies in our lab support the notion that this approach can inhibit certain molecular functions of WBP2 (data not shown).…”

Section: Wbp2 Molecular Interactions and Rational Drug Designmentioning

confidence: 99%

The emerging roles of WBP2 oncogene in human cancers

et al. 2020

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WW domain-binding protein 2 (WBP2) is an emerging oncoprotein. Over the past decade, WBP2 surfaced as a key node connecting key signaling pathways associated with ER/PR, EGFR, PI 3 K, Hippo, and Wnt in cancer. In addition to the oncogenic functions of WBP2, this review discusses the latest research regarding the multilevel regulation and modes of action of WBP2 and how they can be exploited for molecular medicine. In translational research, evidence supports the role of WBP2 as a biomarker for early detection, prognosis, and companion diagnostics in breast cancer. Finally, we envision new trends in WBP2 research in the space of molecular etiology of cancer, targeted therapeutics, and precision medicine.

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Section: Wbp2 Molecular Interactions and Rational Drug Designmentioning

confidence: 99%

The emerging roles of WBP2 oncogene in human cancers

et al. 2020

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“…The authors showed induced degradation of α-synuclein through proteasome pathway and achieved beneficial functional effects: rescue of the mitochondrial dysfunction in a cell model and in primary neurons [34]. It is noteworthy that this strategy of affinity-binding and concomitant initiation of cellular degradation of the target protein is similar to the one described above [29] and may prove to be an efficient biomodulation strategy.…”

Section: Trans-bbb Delivery and Targeting Cnsmentioning

confidence: 84%

“…The authors demonstrated the method with estrogen receptorpositive breast cancers and thus, in their example, the target protein to be degraded was estrogen receptor targeting ligand. As a result, the authors achieved efficient cytotoxic effects on estrogen receptor-positive cancer cells, as well as cancer growth inhibition in a mouse model [29].…”

Section: Targeting Protein-protein Interactionsmentioning

confidence: 97%

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Kurrikoff

Vunk

Langel

2020

Expert Opinion on Biological Therapy

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Introduction: In this review, recent developments and applications with cell-penetrating peptides (CPP) are discussed. CPPs are widely used tools for the delivery of various macromolecular therapeutics, such as proteins and nucleic acids. Areas covered: The current review focuses on recent important advances and reports that demonstrate high clinical and translational potential. Most important clinical developments have occurred with the CPP-drug conjugate approaches that target various protein-protein interactions, and these have been highlighted subsequently. Most of the applications are targeting cancer, but recently, noteworthy advances have taken place in the field of antisense oligonucleotides and muscular dystrophies, lung targeting, and trans-BBB targeting. Expert opinion: Successful applications and clinical development with the drug conjugate approaches are discussed. On the other hand, the reasons of why the nanoparticle approaches are not as far in development are analyzed.

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“…Considering their inability to target “undruggable” proteins with large shallow surface, researchers have drawn their attentions towards specific binding peptides, which have advantages of lower production cost and amenability to chemical synthesis 70 . Compared to small molecules, peptides possess greater potential in structural modification by point mutation or truncation 34 , 71 , 72 . Generally, based on the crystal structure of endogenous complex of POI and binding protein, the key interacting residues can be analyzed to design the peptide targeting warheads 73 .…”

Section: Design and Synthesis Of Lytac And Abtacmentioning

confidence: 99%

Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins

Lin¹,

Jin²,

Shen³

et al. 2021

Theranostics

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Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as “undruggable” before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.

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Development of cell-permeable peptide-based PROTACs targeting estrogen receptor α

Cited by 31 publications

References 34 publications

The emerging roles of WBP2 oncogene in human cancers

The emerging roles of WBP2 oncogene in human cancers

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins

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