Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Adicionar filtros








Intervalo de ano
1.
Acta Pharmaceutica Sinica B ; (6): 533-578, 2024.
Artigo em Inglês | WPRIM | ID: wpr-1011275

RESUMO

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

2.
Frontiers of Medicine ; (4): 823-854, 2023.
Artigo em Inglês | WPRIM | ID: wpr-1010822

RESUMO

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.


Assuntos
Humanos , Ciclo Celular/fisiologia , Divisão Celular , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo
3.
Acta Pharmaceutica Sinica B ; (6): 1686-1698, 2023.
Artigo em Inglês | WPRIM | ID: wpr-982798

RESUMO

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.

4.
Journal of China Pharmaceutical University ; (6): 270-278, 2021.
Artigo em Chinês | WPRIM | ID: wpr-881384

RESUMO

@#Bromodomain-containing protein 4 (BRD4), a new target for tumor therapy, is the most important member of the bromodomain and extra-terminal family. The overexpression of BRD4 is associated with genesis and development of various cancers.Used either alone or in combination with other treatments such as chemotherapy, photothermal therapy and immunotherapy, the BRD4 inhibitors or degraders exhibited excellent antitumor effects, providing a new direction in tumor treatment. In this review, the structure and function of BRD4, the inhibition strategies of BRD4, the application in tumor combination therapy and drug resistance are introduced, which provides reference for targeting BRD4 in tumor therapy.

5.
Chinese Journal of Clinical Oncology ; (24): 586-589, 2020.
Artigo em Chinês | WPRIM | ID: wpr-861621

RESUMO

Fulvestrant is a selective estrogen receptor degrader (SERD), that can specifically bind to estrogen receptor (ER), block ER transcription activity, and induce the degradation of ER protein. However, along with its widespread use in breast cancer endocrine therapy, drug resistance does gradually develop. A better understanding of mechanisms on fulvestrant resistance and the exploration on precise targeted therapy is the key to breaking through treatment bottlenecks and subsequently improving the prognosis of patients. Here, we review research advances in the potential mechanisms of fulvestrant resistance and outline promising approaches such as combination therapy to overcome the resistance.

6.
Acta Pharmaceutica Sinica ; (12): 1801-1810, 2017.
Artigo em Chinês | WPRIM | ID: wpr-779792

RESUMO

Proteolysis-targeting chimeras (PROTACs) are small-molecule protein degraders based on the ubiquitin-proteasome system. Recently, the development of specific small-molecule ligands for several E3 ligases (CRL4CRBN, CRL2VHL and cIAP) have significantly advanced the PROTACs technology. Several PROTACs against various oncogenic proteins including bromodomain-containing protein 4 (BRD4), estrogen receptor (ER) and androgen receptor (AR) have been developed and considered a novel approach for therapy of cancers. There are advantages of the new technology over the traditional small-molecule strategies. This review article provides a summary on the recent progress in the small-molecule-based PROTACs as antitumor drugs, and the challenges of this technology.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA