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A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy
Jinpeng Wang1, Yuechen Wang1, Fenfang Yang2
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
ACS Chemical Biology
|April 25, 2024
Summary
We developed a novel split-and-mix chaperone-mediated autophagy-based degrader (SM-CMAD) platform for targeted protein degradation. This versatile system efficiently degrades multiple targets, offering a promising approach for drug development, especially for previously undruggable proteins.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Development
Background:
- Targeted protein degradation is crucial in drug discovery.
- Lysosomal degraders offer a broader target range than proteasomal ones, ideal for undruggable proteins.
Purpose of the Study:
- To develop a novel lysosome-based degrader platform using split-and-mix PROTAC (SM-PROTAC) technology.
- To create a facile screening system for chaperone-mediated autophagy-based degraders (SM-CMAD).
Main Methods:
- Applied peptide self-assembly based SM-PROTAC technology.
- Developed SM-CMAD for lysosome-based protein degradation.
- Screened SM-CMAD for degradation of ERα, AR, MEK1/2, and BCR-ABL.
Main Results:
- Demonstrated SM-CMAD as a universal platform for targeted protein degradation.
- Successfully degraded multiple targets including ERα, AR, MEK1/2, and BCR-ABL.
- SM-CMAD allows facile screening with programmable ligand ratios.
Conclusions:
- SM-CMAD is a versatile platform for developing lysosome-based degraders.
- This technology facilitates the degradation of challenging protein targets.
- SM-CMAD holds potential for developing multifunctional molecules and advancing clinical translation.
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