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

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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.

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关键词： p300/CBP PROTACs RNF126

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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.

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出版当年[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

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

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出版当年[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CHEMISTRY, ORGANIC

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]

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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.

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