2. Academic Validation
  3. Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors

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.
Stefanie Hauck 1,  Kerstin Hiesinger 2,  Sabrina Khageh Hosseini 1,  Janosch Achenbach 2,  Ricardo M Biondi 3,  Ewgenij Proschak 4,  Martin Zörnig 5,  Dalibor Odadzic 6
Affiliations

Affiliations

  • 1 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Straße 42-44, D-60596 Frankfurt/Main, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany.
  • 3 Department of Internal Medicine I, University Hospital Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • 4 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany. Electronic address: Proschak@pharmachem.uni-frankfurt.de.
  • 5 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Straße 42-44, D-60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: Zoernig@gsh.uni-frankfurt.de.
  • 6 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
PMID: 27729195 DOI: 10.1016/j.bmc.2016.09.015
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100758
    99.72%, FUBP1 Inhibitor