Piperlongumine conjugates induce targeted protein degradation

Jing Pei, Yufeng Xiao, Xingui Liu, Wanyi Hu, Amin Sobh, Yaxia Yuan, Shuo Zhou, Nan Hua, Samuel G. Mackintosh, Xuan Zhang, Kari B. Basso, Manasi Kamat, Qingping Yang, Jonathan D. Licht, Guangrong Zheng, Daohong Zhou, Dongwen Lv

Producción científica: Articlerevisión exhaustiva

22 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)203-213.e17
PublicaciónCell Chemical Biology
Volumen30
N.º2
DOI
EstadoPublished - feb 16 2023

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology

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