Piperlongumine (PL) conjugates induce targeted protein degradation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA851461 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19774160.fastq.gz | Fastqsanger.gz | |||
| SRR19774161.fastq.gz | Fastqsanger.gz | |||
| SRR19774162.fastq.gz | Fastqsanger.gz | |||
| SRR19774163.fastq.gz | Fastqsanger.gz | |||
| SRR19774164.fastq.gz | Fastqsanger.gz |
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Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. To evaluate the specificity of the PL-SNS-032 lead conjugate named 955, TMT-based proteomics were conducted to compare 955 with its warhead SNS-032 in MOLT4 cells. As expected, cells exhibited a significant reduction of CDK9 after treatment with 0.1 µM 955 for 1 h and 6 h while treatment with 1 µM SNS-032 for 6 h had no significant effect on CDK9. Interestingly, 955, but not SNS-032, can also potently degrade CDK10.
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Project description:Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. The lead conjugate 955 can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cells in vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
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