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Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway

Yeongju Lee1, Jiwon Heo2, Hoibin Jeong3

  • 1Department of Chemistry and Division of Advanced Materials Science, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, South Korea.

Angewandte Chemie (International Ed. in English)
|October 7, 2020
PubMed

Insights

Scientists developed a novel proteolysis targeting chimera (PROTAC) to degrade steroid receptor coactivator-1 (SRC-1), a protein linked to cancer progression. This new chemical tool effectively reduced cancer cell invasion and migration, offering a promising strategy for cancer research.

Area of Science:

  • Oncology
  • Molecular Biology
  • Chemical Biology

Background:

  • Aberrant expression of steroid receptor coactivator-1 (SRC-1) is linked to cancer progression and metastasis.
  • Targeting SRC-1 is a potential therapeutic strategy for various cancers.

Purpose of the Study:

  • To develop and characterize a novel proteolysis targeting chimera (PROTAC) for targeted SRC-1 degradation.
  • To investigate the efficacy of the SRC-1 PROTAC in suppressing cancer cell invasion and migration.

Main Methods:

  • Design and synthesis of a bifunctional PROTAC molecule linking an SRC-1 binder to a UBR box E3 ligase ligand.
  • Assessment of SRC-1 degradation in cells via the N-degron pathway.
  • In vitro and in vivo evaluation of the PROTAC's effect on cancer cell invasion and migration.

Main Results:

  • The developed PROTAC efficiently and selectively induced SRC-1 degradation through the N-degron pathway.
  • The SRC-1 degrader significantly suppressed cancer cell invasion and migration both in vitro and in vivo.
  • The UBR box-based PROTAC strategy demonstrated broad applicability across cell types.

Conclusions:

  • The novel SRC-1 PROTAC serves as a valuable chemical tool for studying SRC-1 functions in cancer.
  • PROTACs utilizing the N-degron pathway represent a versatile strategy for degrading disease-associated proteins.
  • Targeted SRC-1 degradation holds potential for inhibiting cancer progression and metastasis.
Keywords:
SRC-1 transcriptional co-activatorcancer metastasisproteolysis-targeting chimers (PROTACs)stapled peptidethe N-degron pathway

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