Lysosome-targeting chimaeras for degradation of extracellular proteins

Banik, Steven M.; Pedram, Kayvon; Wisnovsky, Simon; Ahn, Green; Riley, Nicholas M.; Bertozzi, Carolyn R.

doi:10.1038/s41586-020-2545-9

Cited by 609 publications

(714 citation statements)

References 44 publications

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“…Rather than delineating individual E2/E3-substrate pairings and subsequently subjecting the specific binding interface to a small molecule library screen, these new strategies co-opt endogenous protein degradation machineryspecifically the UPS (i.e. PROTACs, HyT, molecular glues), autophagy (AUTACs) and the endosomal/lysosomal (LYTACs) pathways (398). PROTACs are heterobifunctional molecules which can recruit E3 ubiquitin ligases to the desired protein targets, thereby co-opting the endogenous UPS for targeted protein degradation.…”

Section: Future Opportunities For Gbm Therapeuticsmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

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Section: Future Opportunities For Gbm Therapeuticsmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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“…C) ring‐opening metathesis polymerization of mucin mimics from glycosylated α‐Norbornenyl monomers [67] . D) synthesis of mannose‐6‐phosphonate‐serine and alanine containing polypeptide from mannose pentaacetate [68] …”

Section: Synthetic Mucinsmentioning

confidence: 99%

Design and Synthesis of Mucin‐Inspired Glycopolymers

2020

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Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology includes cell‐cell recognition, signaling, protection, adhesion, and lubrication. Because of their attractive and diverse properties, mucins have recently become the focus of synthetic efforts by researchers who hope to understand and emulate these biomaterials. This review is focused on the development of methodologies for preparing mucin‐inspired synthetic oligomers and glycopolymers, including solid‐phase synthesis, polymerization of glycosylated monomers, and post‐polymerization grafting of glycans to polymer chains. How these synthetic mucins have been used in health applications is discussed. Natural mucins are formed from a conserved set of monomers that are combined into chains of different sequences and lengths to achieve materials with widely diverse properties. Adopting this design paradigm from natural mucins could lead to next‐generation bioinspired synthetic materials.

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“…One is an antibody to POI, the other is a 20‐ or 90‐mer of mannose‐6‐phosphate (M6P) attached to the antibody by forming covalent interaction [16] . Pleasingly, the LYTAC technology may be applied to degrade some intracellular proteins and membrane‐bound proteins such as EGFR, which are typically blind spots of PROTAC [16] . From this perspective, the emergence of LYTAC just offset a few limitations of PROTAC.…”

Section: Advances Of Protac In Diseasesmentioning

confidence: 99%

PROTAC: A Novel Technology for Drug Development**

Liu

2020

ChemistrySelect

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Proteolysis targeting chimeras(PROTACs)as a novel protein degradation technology is opening up a burgeoning field which will bring surprises to drug design and development. PROTACs have attracted a great deal of attention in drug discovery due to their unique mechanism. In recent years, studies on PROTAC have made increasing and vital progresses. In this review, we briefly describe the mechanism and development of PROTAC technology. Then, emphasis is placed on the application of PROTAC technology in several diseases including cancer, neuro-degenerative diseases, autoimmune diseases and viral infections. In addition, a series of bio-techniques relate to PROTACs established in recent years will also be discussed. Finally, we discuss the opportunities and challenges associated with PROTAC technology and analyze some potential future challenges.

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Lysosome-targeting chimaeras for degradation of extracellular proteins

Cited by 609 publications

References 44 publications

Targeting the Ubiquitin System in Glioblastoma

Targeting the Ubiquitin System in Glioblastoma

Design and Synthesis of Mucin‐Inspired Glycopolymers

PROTAC: A Novel Technology for Drug Development**

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