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Inhibition of CREB Binding and Function with a Dual-Targeting Ligand

Yejun Liu1,2, Stephen T Joy1, Madeleine J Henley1,2

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.

Biochemistry
|December 12, 2023
PubMed

Insights

Researchers developed CREBLL-tide, a potent peptide inhibitor targeting the CBP/p300 KIX domain and CREB interaction. This peptide shows promise in inhibiting cancer cell proliferation, particularly in breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • CBP/p300 acts as a transcriptional coactivator, regulating gene expression through interactions with activators.
  • Dysregulation of protein-protein interactions (PPIs) involving the CBP/p300 KIX domain is linked to various cancers.
  • The KIX domain is challenging to drug due to its shallow binding surfaces.

Purpose of the Study:

  • To develop a novel, potent inhibitor of the KIX-CREB PPI.
  • To evaluate the anti-cancer potential of new KIX-targeting peptides.
  • To expand the dual-targeting strategy for inhibiting transcriptional coactivators.

Main Methods:

  • Design and synthesis of a second-generation branched peptide analogue, CREBLL-tide.
  • Assessment of CREBLL-tide's potency and selectivity against KIX-CREB PPI.
  • Evaluation of CREBLL-tide's antiproliferation activity in breast cancer cells.

Main Results:

  • CREBLL-tide demonstrated higher potency and selectivity in inhibiting the KIX-CREB PPI compared to previous analogues.
  • The most effective CREBLL-tide analogue exhibited significant and selective antiproliferation activity in breast cancer cells.
  • The study validates CREBLL-tide as a tool for studying KIX-activator roles in cancer.

Conclusions:

  • CREBLL-tide represents an advanced peptide inhibitor for the KIX-CREB interaction.
  • This peptide shows therapeutic potential for breast cancer treatment.
  • The findings support a dual-targeting strategy for inhibiting coactivator-mediated gene activation in cancer.

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