7rn5

Publication Abstract from PubMed

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.

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen.,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, Tellers DM ACS Med Chem Lett. 2020 Dec 23;12(1):99-106. doi: 10.1021/acsmedchemlett.0c00551. , eCollection 2021 Jan 14. PMID:33488970^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.