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Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to seco -Duocarmycins Targeting the Thioredoxin System.

Jan G FelberAnnabel KitowskiLukas ZeiselMartin S MaierConstanze HeiseJulia AhlfeldOliver Thorn-Seshold
Published in: ACS central science (2023)
Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) system. The Trx system is a critical cellular redox axis that is tightly linked to dysregulated redox/metabolic states in cancer, yet it cannot be addressed by current bioreductive prodrugs, which mainly cluster around oxidized nitrogen species. We instead harnessed Trx/TrxR-specific artificial dichalcogenides to gate the bioactivity of 10 "off-to-on" reduction-activated duocarmycin prodrugs. The prodrugs were tested for cell-free and cellular reductase-dependent activity in 177 cell lines, establishing broad trends for redox-based cellular bioactivity of the dichalcogenides. They were well tolerated in vivo in mice, indicating low systemic release of their duocarmycin cargo, and in vivo anti-tumor efficacy trials in mouse models of breast and pancreatic cancer gave promising indications of effective tumoral drug release, presumably by in situ bioreductive activation. This work therefore presents a chemically novel class of bioreductive prodrugs against a previously unaddressed reductase chemotype, validates its ability to access in vivo -compatible small-molecule prodrugs even of potently cumulative toxins, and so introduces carefully tuned dichalcogenides as a platform strategy for specific bioreduction-based release.
Keyphrases
  • small molecule
  • drug release
  • cell free
  • papillary thyroid
  • drug delivery
  • cancer therapy
  • protein protein
  • mouse model
  • squamous cell
  • metabolic syndrome
  • skeletal muscle
  • adipose tissue