European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 254, С. 115381 - 115381
Опубликована: Апрель 14, 2023
Язык: Английский
Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1694 - 1703
Опубликована: Июнь 14, 2022
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. now emerging as targets for new therapeutic development. Blocking the function of any can be a control agent diseases, such cancer. Traditional drugs like enzyme inhibitors protein–protein have many limitations. The efficacy them remains to proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) become an advanced tool in intervention they remove disease-causing proteins. Extremely potent efficacious small-molecule PROTACs proteins, based on available, potent, selective inhibitors, been reported. This review presents comprehensive overview development regulation cancer, chances challenges associated with this area also highlighted.
Язык: Английский
Процитировано
24
European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 265, С. 116041 - 116041
Опубликована: Дек. 13, 2023
Язык: Английский
Процитировано
14
Acta Materia Medica, Год журнала: 2024, Номер 3(1)
Опубликована: Янв. 1, 2024
Endocrine therapy which blocking the signaling of estrogen receptor, has long been effective for decades as a primary treatment choice breast cancer patients expressing ER. However, issue drug resistance poses significant clinical challenge. It's critically important to create new therapeutic agents that can suppress ERα activity, particularly in cases ESR1 mutations. This review highlights recent efforts development next generation ER-targeted agents, including oral selective ER degraders (SERDs), proteolysis targeting chimera (PROTAC) degraders, other innovative molecules such complete receptor antagonists (CERANs) and covalent (SERCAs). The design, efficacy trials each compound were detailed.
Язык: Английский
Процитировано
5
Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 9
Опубликована: Фев. 3, 2022
Classical targeting in cancer focuses on the development of chemical structures able to bind protein pockets with enzymatic activity. Some these molecules are designed ATP side kinase domain avoiding activation and subsequent oncogenic A further improvement agents relies generation non-allosteric inhibitors that once bound limit function by producing a conformational change at and, therefore, augmenting antitumoural potency. Unfortunately, not all proteins have activity cannot be chemically targeted types molecular entities. Very recently, exploiting degradation pathway through ubiquitination proteasomal key target has gained momentum. With this approach, non-enzymatic such as Transcription Factors can degraded. In regard, we provide an overview current applications PROteolysis TArgeting Chimeras (PROTACs) compounds for treatment solid tumours ways overcome their limitations clinical development. Among different constraints development, improvements bioavailability safety, due optimized delivery, seem relevant. context, it is anticipated those pan-essential genes will narrow therapeutic index. article, review advantages disadvantages potential use drug delivery systems improve safety PROTACs.
Язык: Английский
Процитировано
22
Cancers, Год журнала: 2023, Номер 15(3), С. 611 - 611
Опубликована: Янв. 18, 2023
We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on ligand VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor p38α. provide evidence these compounds can induce specific degradation p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. also show p38α-specific soluble aqueous solutions therefore suitable their administration mice. Systemic induces only liver, probably due PROTAC becoming inactivated organ, upon local mammary tumors. Our alternative traditional chemical inhibitors targeting signaling cultured cells vivo.
Язык: Английский
Процитировано
12
Cell Death and Disease, Год журнала: 2024, Номер 15(7)
Опубликована: Июль 13, 2024
Dysfunction of the ubiquitin-proteasome system (UPS) is involved in pathogenesis various malignancies including colorectal cancer (CRC). Ubiquitin domain containing 1 (UBTD1), a ubiquitin-like protein, regulates UPS-mediated protein degradation and tumor progression some types. However, biological function mechanism UBTD1 are far from being well elucidated, its role CRC has not been explored yet. In our study, we analyzed patients' clinical information expression data, found that tissue was significantly higher than adjacent normal tissue. Higher associated with poorer survival more lymph node metastasis. Overexpression could facilitate, while knockdown inhibit cell proliferation migration, respectively. RNA-seq proteomics indicated c-Myc an important downstream target UBTD1. Metabolomics showed products glycolysis pathway were increased overexpression cells. vitro, verified upregulating promoting migration via regulating c-Myc. promoted cells' glycolysis, evidenced by lactate production glucose uptake following overexpression. Mechanistically, prolonged half-life binding to E3 ligase β-transducin repeat-containing (β-TrCP), thereby upregulated rate-limiting enzyme hexokinase II (HK2), enhanced progression. conclusion, study revealed promotes β-TrCP/c-Myc/HK2 pathway, suggesting potential as prognostic biomarker therapeutic CRC.
Язык: Английский
Процитировано
4
Drug Development Research, Год журнала: 2025, Номер 86(1)
Опубликована: Янв. 3, 2025
ABSTRACT Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant (NS) polymers inside the endoplasmic reticulum (ER) neurons, leading to cellular toxicity and neuronal death. To date, there no cure for FENIB, only palliative care available FENIB patients, underlining urgency develop therapeutic strategies. The purpose this work was create system designed testing small molecules able reduce formation NS polymers. Our results show generation characterisation novel cell culture model based on neural stem progenitor cells (NPCs) inducible expression either wild type (WT) or G392E NS, variant that causes severe FENIB. We also report use these lines explore effects four different proteolysis targeting chimaera (PROTAC) compounds, bivalent engineered bind E3 ubiquitin ligase cereblon, through recruiting motif molecule embelin. This approach aims enhance degradation after retro‐translocation cytosol facilitating its proteasome. little variation in levels any compounds tested. In conclusion, sets basis future attempts identify prevent ER cultured cells.
Язык: Английский
Процитировано
0
Therapeutic Advances in Medical Oncology, Год журнала: 2025, Номер 17
Опубликована: Янв. 1, 2025
The enhancer of zeste homolog 2 (EZH2) is a catalytic component Polycomb repressive complex (PRC2) mediating the methylation histone 3 lysine 27 (H3K27me3) and hence epigenetic repression target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles are exerted PRC2-dependent PRC2-independent non-histone proteins, methyltransferase-independent interactions with various proteins contributing to gene expression regulation alterations in protein stability. frequently mutated and/or its deregulated cancer types. sensitivity inhibitors enzymatic activity state-of-the-art approaches deplete chemical degraders discussed. This review also presents clinical trials phases evaluate use inhibitors, both monotherapy combination other agents for treatment patients diverse types cancers.
Язык: Английский
Процитировано
0
Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер 749, С. 151370 - 151370
Опубликована: Янв. 20, 2025
Язык: Английский
Процитировано
0
Archiv der Pharmazie, Год журнала: 2025, Номер 358(4)
Опубликована: Апрель 1, 2025
ABSTRACT Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease‐causing proteins in drug discovery. One E3 ligases which efficient PROTACs been described is Von Hippel‐Lindau factor (VHL). However, development has so far often relied on minimum computational tools, that it mostly based trial‐and‐error process. Therefore, there great need resource‐ and time‐efficient structure‐based or approaches streamline PROTAC design. In this study, we present combined integrates static ternary complex formation, induced‐fit docking, molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived structures VHL PROTACs, reported BRD4, SMARCA2, FAK, WEE1. addition, applied validated model recently in‐house developed FLT3‐targeted (MA49). The results show models generated with protein–protein docking method implemented software MOE high predictive power reproducing experimental 3D structures. different active their respective showed reliability new VHL‐mediated degraders. particular, sensitive structural changes as evidenced by failed binding modes negative controls. Furthermore, MD simulations confirmed stability complexes emphasized importance dynamic studies understanding relationship between structure function.
Язык: Английский
Процитировано
0