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Updated: Jul 24, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

Selective Proteolysis of Activated Transcriptional Factor by NIR-Responsive Palindromic DNA Thalidomide Conjugate

Min Hou^1,2, Rui Guo¹, Tianyu Ren¹

¹State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biomedical Sciences, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.

Small (Weinheim an Der Bergstrasse, Germany)

|July 7, 2023

Abstract:

Dysfunctional transcription factors that activate abnormal expressions of specific proteins are often associated with the progression of various diseases. Despite being attractive drug targets, the lack of druggable sites has dramatically hindered their drug development. The emergence of proteolysis targeting chimeras (PROTACs) has revitalized the drug development of many conventional hard-to-drug protein targets. Here, the use of a palindromic double-strand DNA thalidomide conjugate (PASTE) to selectively bind and induce proteolysis of targeted activated transcription factor (PROTAF) is reported. The selective proteolysis of the dimerized phosphorylated receptor-regulated Smad2/3 and inhibition of the canonical Smad pathway validates PASTE-mediated PROTAF. Further aptamer-guided active delivery of PASTE and near-infrared light-triggered PROTAF are demonstrated. Great potential in using PASTE for the selective degradation of the activated transcription factor is seen, providing a powerful tool for studying signaling pathways and developing precision medicines.

Insights

A novel palindromic DNA conjugate (PASTE) selectively degrades activated transcription factors, offering a new approach for hard-to-drug targets. This PROTAC technology shows promise for precision medicine and studying disease pathways.

Area of Science:

Molecular Biology
Drug Discovery
Biochemistry

Background:

Dysfunctional transcription factors drive disease progression by altering protein expression.
Targeting transcription factors is challenging due to a lack of druggable sites.
Proteolysis targeting chimeras (PROTACs) offer a promising strategy for previously undruggable targets.

Purpose of the Study:

To develop a novel PROTAC technology for selective degradation of activated transcription factors.
To validate the efficacy of the palindromic double-strand DNA thalidomide conjugate (PASTE) in degrading target proteins.
To explore advanced delivery and activation methods for PROTACs.

Main Methods:

Design and synthesis of a palindromic double-strand DNA thalidomide conjugate (PASTE).
Demonstration of selective proteolysis of dimerized phosphorylated receptor-regulated Smad2/3.
Validation of canonical Smad pathway inhibition.
Development of aptamer-guided active delivery and near-infrared light-triggered PROTAF.

Main Results:

PASTE successfully induced selective proteolysis of the targeted activated transcription factor (PROTAF).
The canonical Smad pathway was effectively inhibited, validating PASTE's mechanism.
Aptamer-guided delivery and light-triggered activation of PASTE were successfully demonstrated.
PASTE proved effective in degrading activated transcription factors.

Conclusions:

PASTE represents a powerful new tool for the selective degradation of activated transcription factors.
This technology has significant potential for advancing the study of signaling pathways.
PASTE offers a promising avenue for the development of novel precision medicines.

Read full analysis

Keywords:

TGF-β/Smad aptamer optical control protein degradation transcription factor upconversion nanoparticles (UCNPs)

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