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

doi:10.1021/jm401742r

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

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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 language	English (US)
Pages (from-to)	3939-3965
Number of pages	27
Journal	Journal of medicinal chemistry
Volume	57
Issue number	10
DOIs	https://doi.org/10.1021/jm401742r
State	Published - May 22 2014
Externally published	Yes

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10.1021/jm401742r

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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

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, Minarovits, J, Szathmary, S, Kéri, G & Orfi, 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

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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.",

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AU - Németh, Gábor

AU - Greff, Zoltán

AU - Sipos, Anna

AU - Varga, Zoltán

AU - Székely, Rita

AU - Sebestyén, Mónika

AU - Jászay, Zsuzsa

AU - Béni, Szabolcs

AU - Nemes, Zoltán

AU - Pirat, Jean Luc

AU - Volle, Jean Noël

AU - Virieux, David

AU - Gyuris, Ágnes

AU - Kelemenics, Katalin

AU - Áy, Éva

AU - Minarovits, Janos

AU - Szathmary, Susan

AU - Kéri, György

AU - Orfi, László

PY - 2014/5/22

Y1 - 2014/5/22

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AB - 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.

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

Abstract

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