Targeting CDKs to inhibit the HIV-1 TAT-mediated transcription

The activity of the CDKs is critical for HIV-1 Tat-mediated transcription and represents a promising target for antiviral therapy.(1) Taking advantage of the crystallographic data of CDK9 in complex with flavopiridol,(2) we have recently performed computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti-CDK9 agents based on the 2- phenylquinazolinone scaffold. CDK2, which plays a supportive role within the transcriptional machinery and shares structural features with CDK9, was also inhibited by these derivatives at comparable concentrations. Inhibition of CDKs translated into the ability to interfere selectively with Tat-mediated transactivation of the viral promoter and in the inhibition of HIV-1 reactivation from latently infected cells, with the most potent derivative showing an IC50 = 4.0 μM.(3) Since the identified 2-phenylquinazolinones are still fragments, they are largely optimizable paving the way to derivatives with improved potency. To this end, the available CDK9 and CDK2 experimental structures are under investigation in order to identify the best templates to use in structure-based design efforts. Using these templates, we will design novel derivatives as CDK9 and/or CDK2 inhibitors in an attempt to study the optimal balance between the inhibition of the two enzymes, and also obtain more potent anti HIV-1 activities.