The activity of the cyclin-dependent kinase 9 (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 4.0 μM. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency. Potent fragments! A 2-phenylquinazolinone fragment was initially identified by computational study, which after a first optimization evolved into a series of compounds capable of inhibiting cyclin-dependent kinase 9 (CDK9) activity at micromolar concentrations. The anti-kinase activity translated well into the ability to inhibit Tat-mediated transcription and HIV-1 infectivity in latently infected cells. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computer-aided design, synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 tat-mediated transcription activity

Iraci N.;
2013

Abstract

The activity of the cyclin-dependent kinase 9 (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 4.0 μM. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency. Potent fragments! A 2-phenylquinazolinone fragment was initially identified by computational study, which after a first optimization evolved into a series of compounds capable of inhibiting cyclin-dependent kinase 9 (CDK9) activity at micromolar concentrations. The anti-kinase activity translated well into the ability to inhibit Tat-mediated transcription and HIV-1 infectivity in latently infected cells. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3189055
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