Journal
CHEMMEDCHEM
Volume 8, Issue 12, Pages 1941-1953Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300287
Keywords
antiviral agents; CDK9; computational chemistry; inhibitors; kinases; P-TEFb; Tat-mediated transcription
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Funding
- Italian Ministry of Health (AIDS) [UPR-2009-1301355]
- PRIN [2008CE75SA, 2010W2KM5L_004]
- KU Leuven [GOA 10/014]
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The activity of the cyclin-dependent kinase9 (CDK9) is critical for HIV-1 Tat-mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us 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, with the most potent derivative 37 (2-(4-aminophenyl)-7-chloroquinazolin-4(3H)-one) showing an IC50 value of 4.0M. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.
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