Pharmacophore-inspired discovery of FLT3 inhibitor from kimchi

Food Chem. 2021 Nov 1:361:130139. doi: 10.1016/j.foodchem.2021.130139. Epub 2021 May 18.

Abstract

Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3'-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.

Keywords: Acute myeloid leukemia; Anti-tumor; FLT3 inhibitor; Kimchi; LTr1.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Fermented Foods*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mutation
  • Phosphorylation / drug effects
  • Sorafenib / pharmacology
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Sorafenib
  • FLT3 protein, human
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3