Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors

Bioorg Med Chem Lett. 2017 Nov 15;27(22):4994-4998. doi: 10.1016/j.bmcl.2017.10.012. Epub 2017 Oct 7.

Abstract

A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line.

Keywords: Acute myeloid leukemia (AML); FMS-like tyrosine kinase 3 with internal tandem duplication mutations (FLT3-ITD); Hematopoietic cell kinase (HCK); Pyrrolo[2,3-d]pyrimidine.

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Humans
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-hck / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-hck / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / toxicity
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Pyrroles / toxicity
  • Structure-Activity Relationship
  • Thermodynamics
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Pyrrolo(2,3-d)pyrimidine
  • fms-Like Tyrosine Kinase 3
  • Proto-Oncogene Proteins c-hck