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

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• 作者：Stefanie Hauck^a ; ^&dagger ; ; Kerstin Hiesinger^b ; ^&dagger ; ; Sabrina Khageh Hosseini^a ; Janosch Achenbach^b ; Ricardo M. Biondi^c ; ^d ; Ewgenij Proschak^b ; ^{Proschak@pharmachem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Martin Z&ouml ; rnig^a ; ^d ; ^&Dagger ; ; ^{Zoernig@gsh.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Dalibor Odadzic^b ; ^d ; ^&Dagger ;
• 关键词：FUBP1 ; Transcriptional regulator ; Pyrazolo[1 ; 5a]pyrimidine
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：5717-5729
• 全文大小：4176 K

文摘

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 <strong class="boldFont">6strong>, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC₅₀ value of 11.0 μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound <strong class="boldFont">6strong>, 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.