Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors

Bioorg Med Chem. 2016 Nov 15;24(22):5717-5729. doi: 10.1016/j.bmc.2016.09.015. Epub 2016 Sep 14.


The transcriptional regulator FUSE binding protein 1 (FUBP1) is aberrantly upregulated in various malignancies, fulfilling its oncogenic role by the deregulation of critical genes involved in cell cycle control and apoptosis regulation. Thus, the pharmaceutical inhibition of this protein would represent an encouraging novel targeted chemotherapy. Here, we demonstrate the identification and initial optimization of a pyrazolo[1,5a]pyrimidine-based FUBP1 inhibitor derived from medium throughput screening, which interferes with the binding of FUBP1 to its single stranded target DNA FUSE. We were able to generate a new class of FUBP1 interfering molecules with in vitro and biological activity. In biophysical assays, we could show that our best inhibitor, compound 6, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC50 value of 11.0μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound 6, resulting in reduced cell expansion and induction of cell death. Finally, we provide insights into the corresponding SAR landscape, leading to a prospective enhancement in potency and cellular efficacy.

Keywords: FUBP1; Pyrazolo[1,5a]pyrimidine; Transcriptional regulator.

MeSH terms

  • Cell Death / drug effects
  • DNA Helicases / antagonists & inhibitors*
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • RNA-Binding Proteins
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • FUBP1 protein, human
  • Pyrazoles
  • Pyrimidines
  • RNA-Binding Proteins
  • pyrazolo(1,5-a)pyrimidine
  • DNA Helicases