title: Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors.
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 IC50value 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.
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Straße 42-44, D-60596 Frankfurt/Main, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hauck
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hiesinger
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Straße 42-44, D-60596 Frankfurt/Main, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Khageh Hosseini
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany.
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.affiliation: Department of Internal Medicine I, University Hospital Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany. Electronic address: Proschak@pharmachem.uni-frankfurt.de.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Odadzic
mesh_terms: D016923:Cell Death / Q000187:drug effects; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D011720:Pyrazoles; D011743:Pyrimidines; D016601:RNA-Binding Proteins; C527752:pyrazolo(1,5-a)pyrimidine; D004265:DNA Helicases
keywords: FUBP1; Pyrazolo[1,5a]pyrimidine; Transcriptional regulator