2-Phenylquinazolinone fragment imparts anti-CDKs and anti-HIV activities

The emergence of multidrug resistant viral strains along with the inability of the current drug regimen to completely eradicate the virus in the HIV infected individuals, demands new drugs capable of interfering with alternative targets or steps of the viral replicative cycle. An appealing strategy could be the interference with host factors involved in the Tat-mediated transcription.1 Among them, CDK9, the catalytic subunit of the Positive Transcriptional Elongation Factor b (P-TEFb), plays a pivotal role in sustaining high levels of HIV transcription representing a promising target for antiviral therapy.2 Taking advantage of the crystallographic data of CDK9 in complex with the best characterized inhibitor, flavopiridol,3 we have performed a structure-based drug design that followed by a structural optimization cycle, led to identify and characterize a new class of nontoxic anti-CDK9 chemotypes based on the 2-phenylquinazolinone scaffold. Inhibition of CDK9 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 at low micromolar concentrations. The appeal of the reported 2-phenylquinazolinones is strenghtened by the lack of toxicity in several cell lines. In addition, being still fragments,4 there is plenty of room for optimization to increase both potency and selectivity The whole drug discovery workflow will be the object of the presentation