Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

Molecular Cancer, Год журнала: 2021, Номер 20(1)

Опубликована: Янв. 4, 2021

c-Myc is a transcription factor that constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression mice with only mild fully reversible side effects, suggesting this be viable therapeutic strategy. Here we reassess the challenges directly targeting c-Myc, evaluate lessons learned from current inhibitors, explore how future strategies such as miniaturisation Omomyc E-box binding could facilitate translation inhibitors into clinic.

Язык: Английский

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Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials

The Lancet Neurology, Год журнала: 2022, Номер 21(8), С. 726 - 734

Опубликована: Май 25, 2022

Язык: Английский

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Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

Cell Death and Differentiation, Год журнала: 2021, Номер 28(2), С. 570 - 590

Опубликована: Янв. 7, 2021

Abstract Neurodegenerative diseases are characterised by progressive damage to the nervous system including selective loss of vulnerable populations neurons leading motor symptoms and cognitive decline. Despite millions people being affected worldwide, there still no drugs that block neurodegenerative process stop or slow disease progression. Neuronal death in these is often linked misfolded proteins aggregate within brain (proteinopathies) as a result disease-related gene mutations abnormal protein homoeostasis. There two major degradation pathways rid cell unwanted prevent their accumulation maintain health cell: ubiquitin–proteasome autophagy–lysosomal pathway. Both degradative depend on modification targets with ubiquitin. Aging primary risk factor most Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis. With aging general reduction proteasomal autophagy, consequent increase potentially neurotoxic aggregates β-amyloid, tau, α-synuclein, SOD1 TDP-43. An over-looked yet component ubiquitin, implicating either an adaptive response toxic evidence dysregulated ubiquitin-mediated driving aggregation. In addition, non-degradative ubiquitin signalling critical for homoeostatic mechanisms fundamental neuronal function survival, mitochondrial homoeostasis, receptor trafficking DNA responses, whilst also playing role inflammatory processes. This review will discuss current understanding ubiquitin-dependent processes emergence target development much needed new treat disease.

Язык: Английский

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Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Cell, Год журнала: 2020, Номер 183(6), С. 1714 - 1731.e10

Опубликована: Дек. 1, 2020

Язык: Английский

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E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

SLAS DISCOVERY, Год журнала: 2020, Номер 26(4), С. 484 - 502

Опубликована: Ноя. 4, 2020

Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand treat human disease. A required PROTAC component is ligand binding an E3 ubiquitin ligase, which then joined another protein be degraded via the ubiquitin-proteasome system. The advent nonpeptidic small-molecule ligase ligands, notably for von Hippel-Lindau (VHL) cereblon (CRBN), revolutionized field ushered in design drug-like PROTACs with potent selective degradation activity. first wave drugs now undergoing clinical development cancer, seeking extend repertoire chemistries that allow hijacking ligases improve scope targeted degradation.Here, we briefly review how traditional ligands were discovered, outline approaches have been recently used discover PROTACs. We will take outlook at current future strategies undertaken invoke either target-based screening or phenotypic-based approaches, including use DNA-encoded libraries (DELs), display technologies cyclic peptides, smaller molecular glue degraders, covalent warhead ligands. These ripe expanding space usher other emerging bifunctional modalities proximity-based pharmacology.

Язык: Английский

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Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action

ACS Chemical Biology, Год журнала: 2018, Номер 13(9), С. 2758 - 2770

Опубликована: Авг. 23, 2018

A new generation of heterobifunctional small molecules, termed proteolysis targeting chimeras (PROTACs), targets proteins for degradation through recruitment to E3 ligases and holds significant therapeutic potential. Despite numerous successful examples, PROTAC molecule development remains laborious unpredictable, involving testing compounds end-point activity at fixed times concentrations without resolving or optimizing the important biological steps required process. Given complexity ubiquitin proteasomal pathway, technologies that enable real-time characterization efficacy mechanism action are critical accelerating compound development, profiling, improving guidance chemical structure-activity relationship. Here, we present an innovative, modular live-cell platform utilizing endogenous tagging apply it monitoring PROTAC-mediated bromodomain extra-terminal family members. We show comprehensive recovery profiles each target, precisely quantifying rates, maximal levels ( Dmax), time frame Dmax. These metrics specific member-dependent responses closely associated with key cellular protein interactions Kinetic studies ternary complex stability influences potency efficacy. Meanwhile, level ubiquitination is highly correlated rate, indicating stemming from productive formation main driver rate. The approaches applied here highlight which choice ligase handle can elicit different outcomes discern individual parameters degradation, ultimately enabling design strategies rank ordering potential compounds.

Язык: Английский

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Current strategies for the design of PROTAC linkers: a critical review

Exploration of Targeted Anti-tumor Therapy, Год журнала: 2020, Номер 1(5)

Опубликована: Окт. 11, 2020

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind E3 ubiquitin ligase and a “warhead” protein interest, connected by chemical linker. Targeted degradation PROTACs has emerged as new modality for the knock down range proteins, with first agents now reaching clinical evaluation. It become increasingly clear that length composition linker play critical roles on physicochemical properties bioactivity PROTACs. While design historically received limited attention, PROTAC field is evolving rapidly currently undergoing important shift from synthetically tractable alkyl polyethylene glycol more sophisticated functional linkers. This promises unlock wealth novel enhanced therapeutic intervention. Here, authors provide timely overview diverse classes in published literature, along their underlying principles overall influence associated Finally, analysis current strategies assembly. The highlight limitations traditional “trial error” approach around selection, suggest potential future avenues further inform rational accelerate identification optimised In particular, believe advances computational structural methods will essential role gain better understanding structure dynamics ternary complexes, be address gaps knowledge design.

Язык: Английский

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Degradation of proteins by PROTACs and other strategies

Acta Pharmaceutica Sinica B, Год журнала: 2019, Номер 10(2), С. 207 - 238

Опубликована: Авг. 13, 2019

Blocking the biological functions of scaffold proteins and aggregated is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be solution, considering its ability to selectively degrade target proteins. Recent progress in strategy include identification structure first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), ARV-110 has entered clinical trials for treatment prostate cancer 2019. These discoveries strongly proved value strategy. In this perspective, we summarized recent meaningful research PROTAC, including types degradation proteins, preliminary data vitro vivo, new E3 ubiquitin ligases. Importantly, molecular design, optimization application candidate molecules are highlighted detail. Future perspectives development advanced medical fields have also been discussed systematically.

Язык: Английский

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Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 62(3), С. 1420 - 1442

Опубликована: Янв. 18, 2019

The estrogen receptor (ER) is a validated target for the treatment of receptor-positive (ER+) breast cancer. Here, we describe design, synthesis, and extensive structure–activity relationship (SAR) studies small-molecule ERα degraders based on proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in discovery highly potent effective PROTAC ER degraders, as exemplified by ERD-308 (32). achieves DC50 (concentration causing 50% protein degradation) values 0.17 0.43 nM MCF-7 T47D ER+ cancer cell lines, respectively, induces >95% degradation at concentrations low 5 both lines. Significantly, more complete than fulvestrant, only approved selective degrader (SERD), inhibition proliferation fulvestrant cells. Further optimization may lead to new therapy advanced

Язык: Английский

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The PROTAC technology in drug development

Cell Biochemistry and Function, Год журнала: 2019, Номер 37(1), С. 21 - 30

Опубликована: Янв. 1, 2019

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by molecule. This takes advantage of moiety targeted and recognizing E3 ubiquitin ligase produces hybrid molecule to specifically knock down protein. During first decade, three pedigreed groups worked on development this technology. To date, extended different groups, aiming develop drugs against diseases including cancers. review summarizes contributions PROTAC. Significance study summarized PROTAC readers also presented author's opinions application in tumor therapy.

Язык: Английский

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