title: Novel, selective CDK9 inhibitors for the treatment of HIV infection.
abstract: Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-to-date review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC(50) < 100 nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.
authors.affiliation: Vichem Chemie Research Ltd., Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Németh
authors.forename: Z
authors.initials: Z
authors.lastname: Varga
authors.forename: Z
authors.initials: Z
authors.lastname: Greff
authors.forename: G
authors.initials: G
authors.lastname: Bencze
authors.forename: A
authors.initials: A
authors.lastname: Sipos
authors.forename: C
authors.initials: C
authors.lastname: Szántai-Kis
authors.forename: F
authors.initials: F
authors.lastname: Baska
authors.forename: A
authors.initials: A
authors.lastname: Gyuris
authors.forename: K
authors.initials: K
authors.lastname: Kelemenics
authors.forename: Z
authors.initials: Z
authors.lastname: Szathmáry
authors.forename: J
authors.initials: J
authors.lastname: Minárovits
authors.forename: G
authors.initials: G
authors.lastname: Kéri
authors.forename: L
authors.initials: L
authors.lastname: Orfi
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D042863:Cyclin-Dependent Kinase 9; C030986:pyrimidine