Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase

J Enzyme Inhib Med Chem. 2018 Dec;33(1):74-84. doi: 10.1080/14756366.2017.1376666.

Abstract

Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition.

Keywords: Pyrrolo[2,3-d]pyrimidines; aurora kinase inhibitors; epidermal growth factor receptor kinase inhibitors.

MeSH terms

  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship

Substances

  • N4-(4-methoxyphenyl)-7H-pyrrolo(2,3-d)pyrimidine-4-amine
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • ErbB Receptors
  • AURKA protein, human
  • Aurora Kinase A

Grants and funding

This study was supported in part by the Roosevelt University College of Pharmacy Intramural Grant and Faculty Summer Research Grant (SK). UK received support from the German Cancer Consortium (DKTK) and the German Cancer Research Center (DKFZ), and Deutsche Forschungsgemeinschaft (SFB 824).