title: Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.
abstract: Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.
authors.affiliation: Molecular Biology Program and the Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Chao
authors.forename: K
authors.initials: K
authors.lastname: Fujinaga
authors.forename: J E
authors.initials: JE
authors.lastname: Marion
authors.forename: R
authors.initials: R
authors.lastname: Taube
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: A M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: B M
authors.initials: BM
authors.lastname: Peterlin
authors.forename: D H
authors.initials: DH
authors.lastname: Price
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D000255:Adenosine Triphosphate; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases