Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen
Year: 2020
Type: article
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.
Source: ACS Medicinal Chemistry Letters
Authors: Marina Bukhtiyarova, Erica M. Cook, Paula J. Hancock, Alan W. Hruza, Anthony W. Shaw, Gregory C. Adam, Richard J. O. Barnard, Philip M. McKenna, M. Katharine Holloway, Ian M. Bell, Steve Carroll, Ivan Cornella-Taracido, Christopher D. Cox, Peter S. Kutchukian, David A. Powell, Corey Strickland, B. Wesley Trotter, Matthew Tudor, Scott Wolkenberg, Jing Li, David M. Tellers
Institution: Merck & Co., Inc., Rahway, NJ, USA (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3115187614