Cathepsin D inhibitors based on tasiamide B derivatives with cell membrane permeability

Bioorg Med Chem. 2022 Mar 1:57:116646. doi: 10.1016/j.bmc.2022.116646. Epub 2022 Jan 30.

Abstract

Cathepsin D (Cath D) has been evidenced as a potential target for cancer therapy. Our previous studies revealed that TB-9, a tasiamide B derivative, exhibited highly potent inhibition against Cath D with satisfactory selectivity over Cath E and BACE1. But this compound was inactive on cell level possibly due to poor membrane permeability. Herein, we report the design, synthesis, and evaluation of two novel Cath D inhibitors (2 and 3) which combining tasiamide B scaffold with a cell penetrating peptide (CPP) specifically targeting the endolysosomal compartment. The results revealed that 2 and 3 not only retained highly potent inhibition against Cath D, but also were active against MDA-MB-231 cell lines.

Keywords: Anti-cancer; Bioconjugate; Cathepsin D inhibitors; Cell penetrating peptide; Tasiamide B derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cathepsin D / antagonists & inhibitors*
  • Cathepsin D / metabolism
  • Cell Membrane Permeability / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Protease Inhibitors
  • tasiamide B
  • CTSD protein, human
  • Cathepsin D