Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock

Commun Biol. 2021 Oct 7;4(1):1165. doi: 10.1038/s42003-021-02701-1.


Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3-FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Carcinogenesis / drug effects*
  • Cell Line, Tumor
  • Fluoresceins / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / genetics
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Shock, Septic / drug therapy*


  • APBA3 protein, human
  • Adaptor Proteins, Signal Transducing
  • Fluoresceins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • naphthofluorescein
  • Mixed Function Oxygenases
  • HIF1AN protein, human