详情页 - 四川省肿瘤医院知识库

当前位置：首页 > 详情页

Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders

35| 认领 | 导出 | 链接全文 |

文献详情

资源类型：

WOS体系：

Pubmed体系：

收录情况： ◇ SCIE

作者：

机构： [1]Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China. [2]Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology, Chengdu, China.

出处：

DOI：

ISSN：

关键词： p300/CBP PROTACs RNF126

摘要：

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.Copyright © 2024 Elsevier Inc. All rights reserved.

基金：

语种：

被引次数：

WOS：

PubmedID：

中科院(CAS)分区：

出版当年[2024]版：

无

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区有机化学 2 区生化与分子生物学

JCR分区：

出版当年[2024]版：

无

最新[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CHEMISTRY, ORGANIC

影响因子： 4.5 最新[2023版] 4.7 最新五年平均 4.5 出版当年[2023版] 0 出版当年五年平均 4.5 出版前一年[2023版]

第一作者：

第一作者机构： [1]Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China.

共同第一作者：

通讯作者：

推荐引用方式(GB/T 7714)：

APA：

MLA：

相关文献

[1]Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain. [2]PROTACs in gastrointestinal cancers [3]Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs. [4]Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers [5]Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future [6]Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers. [7]What influences the activity of Degrader-Antibody conjugates (DACs) [8]Discovery of the GSH responsive "Y-PROTACs" targeting ALK and CDK4/6 as a potential treatment for cancer [9]Advancements on Small Molecule PROTACs Containing an Indole/Spiro-fused Oxoindole Scaffolds: An Emerging Degrader Targeting Cancers. [10]Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.