Synthesis and Evaluation of Phosphorus Containing, Specific CDK9/CycT1 Inhibitors

被引：68

作者：

Nemeth, Gabor ^{[1
]}

Greff, Zoltan ^{[1
]}

Sipos, Anna ^{[1
]}

Varga, Zoltan ^{[1
]}

Szekely, Rita ^{[1
]}

Sebestyen, Monika ^{[2
]}

Jaszay, Zsuzsa ^{[2
]}

Beni, Szabolcs ^{[3
]}

Nemes, Zoltan ^{[3
]}

Pirat, Jean-Luc ^{[4
]}

Volle, Jean-Noel ^{[4
]}

Virieux, David ^{[4
]}

Gyuris, Agnes ^{[5
]}

Kelemenics, Katalin ^{[6
]}

Ay, Eva ^{[7
]}

Minarovits, Janos ^{[7
,8
]}

Szathmary, Susan ^{[6
]}

Keri, Gyoergy ^{[1
,9
]}

Orfi, Laszlo ^{[1
,3
]}

机构：

[1] Vichem Chem Ltd, H-1022 Budapest, Hungary

[2] Budapest Univ Technol & Econ, Dept Organ Chem & Technol, H-1111 Budapest, Hungary

[3] Semmelweis Univ, Dept Pharmaceut Chem, H-1092 Budapest, Hungary

[4] ENSCM, Inst Charles Gerhardt, AM2N, UMR5253, F-34296 Montpellier 5, France

[5] RT Europe Res Ctr, H-9200 Mosonmagyarovar, Hungary

[6] GalenBio Ltd, H-9200 Mosonmagyarovar, Hungary

[7] Natl Ctr Epidemiol, Microbiol Res Grp, H-1097 Budapest, Hungary

[8] Univ Szeged, Dept Oral Biol & Expt Dent Res, Fac Dent, H-6720 Szeged, Hungary

[9] Semmelweis Univ, MTA SE Pathobichem Res Grp, Dept Med Chem Mol Biol & Pathobiochem, H-1094 Budapest, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 10期

关键词：

MEDICINAL CHEMISTRY; SIGNAL-TRANSDUCTION; KINASE INHIBITOR; CDK9; INHIBITORS; P-TEFB; TARGET; HIV-1; BIOISOSTERES; MODULATION; MECHANISMS;

D O I：

10.1021/jm401742r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3939 / 3965

页数：27

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