Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen.
ACS Med Chem Lett
; 12(1): 99-106, 2021 Jan 14.
Article
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| MEDLINE
| ID: mdl-33488970
ABSTRACT
By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite 1 lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose 1 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed.
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MEDLINE
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En
Revista:
ACS Med Chem Lett
Año:
2021
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Article
País de afiliación:
Estados Unidos