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Related Experiment Video

Updated: May 8, 2026

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

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Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach.

Fenfang Yang¹, Qinhong Luo^1,2, Yuechen Wang¹

¹State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

Journal of the American Chemical Society

|March 31, 2023

Summary

A novel split-and-mix nanoplatform simplifies the creation of bifunctional molecules for targeted RNA degradation and protein degradation. This platform, demonstrated via split-and-mix proteolysis-targeting chimeras (SM-PROTACs), offers programmable control for diverse therapeutic applications.

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Area of Science:

Biotechnology
Molecular Biology
Drug Discovery

Background:

Developing bifunctional molecules for targeted biomolecule regulation (RNA degradation, protein acetylation, protein degradation) is complex and time-consuming.
Existing methods require extensive optimization for screening and achieving desired ligand ratios.

Purpose of the Study:

To introduce a novel split-and-mix nanoplatform for facile screening and programmable control of bifunctional molecules.
To demonstrate the platform's utility in creating split-and-mix proteolysis-targeting chimeras (SM-PROTACs) for targeted protein degradation.

Main Methods:

Development of a self-adjustable nanoplatform enabling programmable ligand ratios and self-optimized biomolecule spatial recognition.
Application of the nanoplatform to synthesize SM-PROTACs targeting various intracellular proteins (ERα, CDK4/6, AR, MEK1/2, BRD2/4, BCR-ABL).

Main Results:

Successful demonstration of SM-PROTACs for targeted disruption of multiple intracellular therapeutic targets.
Validation of the nanoplatform's effectiveness and universality for proximity-induced applications.
Confirmation of the platform's programmable nature and broad applicability.

Conclusions:

The split-and-mix nanoplatform offers a streamlined approach to developing bifunctional molecules, significantly reducing optimization efforts.
SM-PROTACs represent a powerful application of this platform for targeted protein degradation with potential in various therapeutic areas.
The platform holds significant promise for advancing biomolecule regulation in epigenetics, gene editing, and beyond.