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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Bukhtiyarova M,Cook EM,Hancock PJ,Hruza AW,Shaw AW,Adam GC,Barnard RJO,McKenna PM,Holloway MK,Bell IM,Carroll S,Cornella-Taracido I,Cox CD,Kutchukian PS,Powell DA,Strickland C,Trotter BW,Tudor M,Wolkenberg S,Li J,doi
10.1021/acsmedchemlett.0c00551subject
Has Abstractpub_date
2020-12-23 00:00:00pages
99-106issue
1issn
1948-5875journal_volume
12pub_type
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