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A Multi-Split-and-Mix Platform for a Variety of Targeted Protein Degradation
Yuechen Wang1, Qinhong Luo1, Yun Xing1
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
ACS Chemical Biology
|August 20, 2025
Summary
A novel Multi-SM-PROTAC platform enables simultaneous degradation of multiple protein targets. This bifunctional molecule approach simplifies complex drug development for undruggable targets, showing promise in cancer therapy.
Area of Science:
- Biochemistry and Molecular Biology
- Drug Discovery and Development
- Chemical Biology
Background:
- Proteolysis-targeting chimera (PROTAC) technology offers a novel therapeutic strategy for traditionally undruggable targets.
- PROTAC development, especially for multitargeting applications, faces challenges in design complexity and synthesis cost.
- Existing PROTACs often struggle with simultaneous degradation of multiple targets or efficient multi-E3 ligase engagement.
Purpose of the Study:
- To introduce a novel Multi-Split-and-Mix PROTAC (Multi-SM-PROTAC) platform for efficient simultaneous degradation of multiple protein targets.
- To demonstrate the flexibility and efficacy of the Multi-SM-PROTAC platform in achieving various degradation strategies.
- To showcase the potential of Multi-SM-PROTACs in advancing drug discovery for complex diseases.
Main Methods:
- Utilizing the self-assembly properties of the split-and-mix strategy for PROTAC construction.
- Designing and synthesizing Multi-SM-PROTACs capable of engaging multiple ligands and E3 ligases.
- Experimentally validating the simultaneous degradation of dual targets and multi-E3 ligase-mediated degradation of single or dual targets.
Main Results:
- Successfully demonstrated simultaneous degradation of dual protein targets using the Multi-SM-PROTAC platform.
- Achieved multi-E3 ligase-mediated degradation of single targets, enhancing degradation efficiency.
- Showcased multi-E3 ligase-mediated degradation of dual targets, proving the platform's versatility.
- Validated the platform's ability to achieve multimodule selection and programming for specific therapeutic objectives.
Conclusions:
- The Multi-SM-PROTAC platform offers a flexible and efficient approach to multitargeting protein degradation.
- This novel platform overcomes the complexity and cost associated with traditional PROTAC development.
- Multi-SM-PROTACs hold significant promise for advancing cancer therapy and other disease treatments by enabling precise control over protein degradation.
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