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

Gábor Németh, Zoltán Greff, Anna Sipos, Zoltán Varga, Rita Székely, Mónika Sebestyén, Zsuzsa Jászay, Szabolcs Béni, Zoltán Nemes, Jean Luc Pirat, Jean Noël Volle, David Virieux, Ágnes Gyuris, Katalin Kelemenics, Éva Áy, Janos Minarovits, Susan Szathmary, György Kéri, László Orfi

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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 (US)
Pages (from-to)3939-3965
Number of pages27
JournalJournal of medicinal chemistry
Volume57
Issue number10
DOIs
StatePublished - May 22 2014
Externally publishedYes

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    Németh, G., Greff, Z., Sipos, A., Varga, Z., Székely, R., Sebestyén, M., Jászay, Z., Béni, S., Nemes, Z., Pirat, J. L., Volle, J. N., Virieux, D., Gyuris, Á., Kelemenics, K., Áy, É., Minarovits, J., Szathmary, S., Kéri, G., & Orfi, L. (2014). Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors. Journal of medicinal chemistry, 57(10), 3939-3965. https://doi.org/10.1021/jm401742r