Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil

  • J Med Chem. 2021 Apr 22;64(8):4450-4461. doi: 10.1021/acs.jmedchem.0c00897.
Chun-Kai Chang  1 ,  Pei-Fang Chiu  1 ,  Hui-Yi Yang  1 ,  Yu-Pu Juang  1 ,  Yen-Hsun Lai  1 ,  Tzung-Sheng Lin  1 ,  Lih-Ching Hsu  1 ,  Linda Chia-Hui Yu  2 ,  Pi-Hui Liang  1  3
Affiliations
  • 1. School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 2. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 3. The Genomics Research Center, Academia Sinica, Taipei 128, Taiwan.
PMID: 33819035 DOI: 10.1021/acs.jmedchem.0c00897
Abstract

Overexpression of glucose transporters (GLUTs) in colorectal Cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal Cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.