Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

Wiley Interdisciplinary Reviews - RNA, Год журнала: 2018, Номер 9(4)

Опубликована: Апрель 25, 2018

Defects in alternative splicing are frequently found human tumors and result either from mutations splicing‐regulatory elements of specific cancer genes or changes the regulatory machinery. RNA regulators have emerged as a new class oncoproteins tumor suppressors, contribute to disease progression by modulating isoforms involved hallmark pathways. Thus, dysregulation is fundamental provides potentially rich source novel therapeutic targets. Here, we review alterations factors detected tumors, well resulting alternatively spliced that impact hallmarks, discuss how they pathogenesis. highly regulated process and, such, themselves tightly regulated. Differential transcriptional posttranscriptional regulation modulates their levels activities cells. Furthermore, composition microenvironment can also influence which expressed given cell type drug responses. Finally, summarize current efforts targeting splicing, including global inhibition using small molecules blocking spliceosome splicing‐factor‐modifying enzymes, splice‐switching RNA‐based therapeutics modulate cancer‐specific isoforms. This article categorized under: Disease Development > Processing Splicing Regulation/Alternative

Язык: Английский

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Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Май 18, 2021

Abstract Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way modulate protein homeostasis for therapy; however, the always-on bioactivity existing PROTACs potentially leads uncontrollable degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPN pro ) phototherapeutic activatable abilities photo-immunometabolic therapy. SPN can remotely generate singlet oxygen ( 1 O 2 under NIR photoirradiation eradicate tumor cells induce immunogenic cell death (ICD) enhance immunogenicity. Moreover, PROTAC function is specifically activated by biomarker (cathepsin B) trigger targeted proteolysis immunosuppressive indoleamine 2,3-dioxygenase (IDO) living mice. The persistent IDO blocks tryptophan (Trp)-catabolism program promotes activation effector T cells. Such SPNpro-mediated in-situ immunometabolic synergizes phototherapy boost antitumor T-cell immunity, effectively inhibiting growth metastasis. Thus, this study provides platform advance

Язык: Английский

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The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

Nature, Год журнала: 2020, Номер 585(7824), С. 293 - 297

Опубликована: Июнь 3, 2020

Язык: Английский

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Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Journal of Medicinal Chemistry, Год журнала: 2018, Номер 62(2), С. 699 - 726

Опубликована: Дек. 12, 2018

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be lengthy unpredictable process, it remains unclear whether any combination might productive for degradation. We describe probe-quality degrader ligase–target pair deemed unsuitable: von Hippel–Lindau (VHL) BRD9, bromodomain-containing subunit SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns linkers monitoring cellular degradation activities, kinetic profiles, ubiquitination, as well ternary formation thermodynamics. The emerged structure–activity relationships guided discovery VZ185, potent, fast, selective BRD9 its close homolog BRD7. Our findings qualify new chemical tool BRD7/9 knockdown provide roadmap PROTAC development against seemingly incompatible target–ligase combinations.

Язык: Английский

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Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Cancer Cell, Год журнала: 2019, Номер 35(3), С. 369 - 384.e7

Опубликована: Фев. 23, 2019

Язык: Английский

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Aberrant RNA Splicing in Cancer

Annual Review of Cancer Biology, Год журнала: 2018, Номер 3(1), С. 167 - 185

Опубликована: Ноя. 28, 2018

RNA splicing, the enzymatic process of removing segments premature to produce mature RNA, is a key mediator proteome diversity and regulator gene expression. Increased systematic sequencing genome transcriptome cancers has identified variety means by which splicing altered in cancer relative normal cells. These findings, combination with discovery recurrent change-of-function mutations factors cancers, suggest that alterations are drivers tumorigenesis. Greater characterization parallels increasing efforts pharmacologically perturb early-phase clinical development small molecules disrupt patients cancer. Here we review recent studies global changes cancer, regulation mitogenic pathways critical transformation, therapeutically target

Язык: Английский

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Rational discovery of molecular glue degraders via scalable chemical profiling

Nature Chemical Biology, Год журнала: 2020, Номер 16(11), С. 1199 - 1207

Опубликована: Авг. 3, 2020

Язык: Английский

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WD40 repeat domain proteins: a novel target class?

Nature Reviews Drug Discovery, Год журнала: 2017, Номер 16(11), С. 773 - 786

Опубликована: Окт. 13, 2017

Язык: Английский

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RNA splicing dysregulation and the hallmarks of cancer

Nature reviews. Cancer, Год журнала: 2023, Номер 23(3), С. 135 - 155

Опубликована: Янв. 10, 2023

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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