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Published on: November 9, 2020
Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders
Yan-Hua Lei1, Qing Tang1, Yang Ni1
1Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China.
Abstract:
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.
Insights
Researchers developed novel PROTACs (proteolysis-targeting chimeras) to degrade p300/CBP proteins, crucial in cancer. The lead compound A8 effectively reduced p300/CBP levels, inhibiting cancer cell growth and inducing apoptosis.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- p300 and CREB-binding protein (CBP) are histone acetyltransferases that activate oncogene transcription.
- Dysregulation of p300/CBP is implicated in various cancers, making them attractive therapeutic targets.
Purpose of the Study:
- To design and synthesize novel small molecule Proteolysis-Targeting Chimeras (PROTACs) targeting p300/CBP.
- To evaluate the efficacy of these PROTACs in degrading p300/CBP and inhibiting cancer cell proliferation.
Main Methods:
- Synthesis of p300/CBP-targeted PROTACs by linking RNF126 E3 ligase and p300/CBP bromodomain ligands.
- Assessment of p300/CBP degradation in cancer cell lines (MV4-11, Molm13) using the lead compound A8.
- Evaluation of A8's effects on cell cycle, apoptosis, and oncogene expression (c-Myc).
Main Results:
- The optimal PROTAC molecule, A8, demonstrated effective and dose-dependent degradation of p300 and CBP via the ubiquitin-proteasome system.
- A8 achieved significant degradation with low nanomolar DC50 values in tested cell lines.
- A8 exhibited antiproliferative activity, induced G0/G1 cell cycle arrest, and promoted apoptosis in p300/CBP-dependent cancer cells, including c-Myc downregulation.
Conclusions:
- A8 represents a promising new chemotype for developing drug-like PROTACs targeting p300/CBP.
- These findings suggest potential applications for p300/CBP-targeting PROTACs in cancer therapy.
