The positive transcription elongation factor (P-TEFb) (CDK9/cyclin T1) regulates RNA Polymerase II dependent transcription of cellular and integrated viral genes. It is an essential cofactor for HIV-1 Tat-transactivation and selective inhibition of P-TEFb blocks HIV-1 replication without affecting cellular transcription, indicating that P-TEFb could be a potential target for developing anti-HIV therapeutics. Flavopiridol, a small molecule CDK inhibitor, blocks HIV-1 Tat-transactivation and viral replication by inhibiting P-TEFb kinase activity, but it is highly cytotoxic. In search for selective and less cytotoxic P-TEFb inhibitors, we prepared a series of flavopiridol analogues and evaluated their kinase inhibitory activity against P-TEFb and CDK2/cyclin A, cellular antiviral potency, and cytotoxicity. We identified several analogues that selectively inhibit P-TEFb kinase activity in vitro and show antiviral potency comparable to that of flavopiridol, but with significantly reduced cytotoxicity. These compounds are valuable molecular probes for understanding P-TEFb-regulated cellular and HIV-1 gene transcription and provide potential anti-HIV-1 therapeutics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.