Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibit
or that is in clinical trials as a cancer treatment because of its antiprol
iferative properties. We found that the flavonoid potently inhibited transc
ription by RNA polymerase II in vitro by blocking the transition into produ
ctive elongation, a step controlled by P-TEFb, The ability of P-TEFb to pho
sphorylate the carboxyl-terminal domain of the large subunit of RNA polymer
ase 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 i
s a required cellular cofactor for the human immunodeficiency virus (HIV-1)
transactivator, Tat, Consistent with its ability to inhibit P-TEFb, flavop
iridol blocked Tat transactivation of the viral promoter in vitro. Furtherm
ore, flavopiridol blocked HIV-1 replication in both single-round and viral
spread assays with an IC50 of less than 10 nM.