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Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone

Meihui Yi1, Fengbin Wang2, Weiyi Tan1

  • 1Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.

Journal of the American Chemical Society
|July 18, 2022
PubMed

Insights

New rigid-rod aromatic molecules target phosphatases in bone metastasis. This approach kills cancer cells in a simulated bone environment by forming nanotube structures.

Area of Science:

  • Biochemistry
  • Materials Science
  • Oncology

Background:

  • Bone metastasis is a significant challenge in cancer therapy.
  • Targeting
  • undruggable
  • enzymes like phosphatases presents a therapeutic opportunity.
  • Developing novel molecules that selectively target the tumor microenvironment (TME) is crucial.

Purpose of the Study:

  • To design and synthesize enzymatic responsive rigid-rod aromatics as substrates for phosphatases.
  • To evaluate the efficacy of these molecules in killing cancer cells within a bone metastasis model.
  • To elucidate the self-assembly mechanism and structural characteristics of these molecules.

Main Methods:

  • Synthesis of pBP-NBD (1P) by phosphorylating and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP).
  • Co-culture experiments with metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells (Saos2).
  • Cryo-electron microscopy (Cryo-EM) to determine nanotube structures at atomic resolution.

Main Results:

  • pBP-NBD (1P) effectively kills both mCRPCs and Saos2 cells in co-culture.
  • 1P rapidly enters Saos2 cells and targets the endoplasmic reticulum (ER).
  • Co-culturing enhances 1P uptake by mCRPCs; Cryo-EM reveals identical helical nanotube packing stabilized by pi-stacking interactions.

Conclusions:

  • Enzymatic responsive rigid-rod aromatics can act as substrates for phosphatases to eliminate cancer cells in a bone metastasis microenvironment.
  • The self-assembled nanotube structures of these molecules are characterized at atomic resolution.
  • This work expands the molecular toolkit for designing enzyme-instructed self-assembling (EISA) substrates targeting the TME.

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