Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells

J Med Chem. 2021 Sep 23;64(18):13475-13486. doi: 10.1021/acs.jmedchem.1c00870. Epub 2021 Sep 10.


Beclin 1 is an essential autophagy gene and a haploinsufficient tumor suppressor. Beclin 1 is the scaffolding member of the Class III phosphatidylinositol-3-kinase complex (PI3KC3) and recruits two positive regulators Atg14L and UVRAG through its coiled-coil domain to upregulate PI3KC3 activity. Our previous work has shown that hydrocarbon-stapled peptides targeted to the Beclin 1 coiled-coil domain reduced Beclin 1 homodimerization and promoted the Beclin 1-Atg14L/UVRAG interaction. These peptides also induced autophagy and enhanced the endolysosomal degradation of cell surface receptors like EGFR. Here, we present the optimization of these Beclin 1-targeting peptides by staple scanning and sequence permutation. Placing the hydrocarbon staple closer to the Beclin 1-peptide interface enhanced their binding affinity by ∼10- to 30-fold. Optimized peptides showed potent antiproliferative efficacy in cancer cells that overexpressed EGFR and HER2 by inducing necrotic cell death but not apoptosis. Our Beclin 1-targeting stapled peptides may serve as effective therapeutic candidates for EGFR- or HER2-driven cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Beclin-1 / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Design
  • ErbB Receptors / metabolism
  • HEK293 Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Necrosis / chemically induced
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Conformation
  • Proteolysis
  • Receptor, ErbB-2 / metabolism


  • Antineoplastic Agents
  • BECN1 protein, human
  • Beclin-1
  • Peptides
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2