Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors

Gábor Németh, Zoltán Greff, Anna Sipos, Z. Varga, Rita Székely, Mónika Sebestyén, Zsuzsa Jászay, S. Béni, Zoltán Nemes, Jean Luc Pirat, Jean Noël Volle, David Virieux, Ágnes Gyuris, Katalin Kelemenics, Éva Áy, J. Mináróvits, Susan Szathmary, G. Kéri, L. Őrfi

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.

Original languageEnglish
Pages (from-to)3939-3965
Number of pages27
JournalJournal of Medicinal Chemistry
Volume57
Issue number10
DOIs
Publication statusPublished - May 22 2014

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Phosphorus
Phosphotransferases
Organophosphonates
Antiviral Agents
Adenosine Triphosphate
HIV
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors. / Németh, Gábor; Greff, Zoltán; Sipos, Anna; Varga, Z.; Székely, Rita; Sebestyén, Mónika; Jászay, Zsuzsa; Béni, S.; Nemes, Zoltán; Pirat, Jean Luc; Volle, Jean Noël; Virieux, David; Gyuris, Ágnes; Kelemenics, Katalin; Áy, Éva; Mináróvits, J.; Szathmary, Susan; Kéri, G.; Őrfi, L.

In: Journal of Medicinal Chemistry, Vol. 57, No. 10, 22.05.2014, p. 3939-3965.

Research output: Contribution to journalArticle

Németh, G, Greff, Z, Sipos, A, Varga, Z, Székely, R, Sebestyén, M, Jászay, Z, Béni, S, Nemes, Z, Pirat, JL, Volle, JN, Virieux, D, Gyuris, Á, Kelemenics, K, Áy, É, Mináróvits, J, Szathmary, S, Kéri, G & Őrfi, L 2014, 'Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors', Journal of Medicinal Chemistry, vol. 57, no. 10, pp. 3939-3965. https://doi.org/10.1021/jm401742r
Németh, Gábor ; Greff, Zoltán ; Sipos, Anna ; Varga, Z. ; Székely, Rita ; Sebestyén, Mónika ; Jászay, Zsuzsa ; Béni, S. ; Nemes, Zoltán ; Pirat, Jean Luc ; Volle, Jean Noël ; Virieux, David ; Gyuris, Ágnes ; Kelemenics, Katalin ; Áy, Éva ; Mináróvits, J. ; Szathmary, Susan ; Kéri, G. ; Őrfi, L. / Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 10. pp. 3939-3965.
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