Modification of a promiscuous inhibitor shifts the inhibition from γ-secretase to FLT-3

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7634-40. doi: 10.1016/j.bmcl.2012.10.016. Epub 2012 Oct 11.

Abstract

The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/γ-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on γ-secretase activity and enhanced FLT-3 inhibition.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Phenotype
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Zebrafish / embryology
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Amyloid Precursor Protein Secretases