title: Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors.
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.
authors.affiliation: Vichem Chemie Ltd. , Budapest 1022, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Németh
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Greff
authors.forename: Anna
authors.initials: A
authors.lastname: Sipos
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Varga
authors.forename: Rita
authors.initials: R
authors.lastname: Székely
authors.forename: Mónika
authors.initials: M
authors.lastname: Sebestyén
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Jászay
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nemes
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pirat
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Volle
authors.forename: David
authors.initials: D
authors.lastname: Virieux
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Gyuris
authors.forename: Katalin
authors.initials: K
authors.lastname: Kelemenics
authors.forename: Eva
authors.initials: E
authors.lastname: Ay
authors.forename: Janos
authors.initials: J
authors.lastname: Minarovits
authors.forename: Susan
authors.initials: S
authors.lastname: Szathmary
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: László
authors.initials: L
authors.lastname: Orfi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D056906:Cyclin T / Q000037:antagonists & inhibitors*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006801:Humans; D010758:Phosphorus; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; C503684:CCNT1 protein, human; D056906:Cyclin T; D047428:Protein Kinase Inhibitors; D010758:Phosphorus; D042863:Cyclin-Dependent Kinase 9