2. Academic Validation
  3. Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen

  • ACS Med Chem Lett. 2020 Dec 23;12(1):99-106. doi: 10.1021/acsmedchemlett.0c00551.
Marina Bukhtiyarova 1,  Erica M Cook 1,  Paula J Hancock 1,  Alan W Hruza 2,  Anthony W Shaw 1,  Gregory C Adam 1,  Richard J O Barnard 1,  Philip M McKenna 1,  M Katharine Holloway 1,  Ian M Bell 1,  Steve Carroll 1,  Ivan Cornella-Taracido 3,  Christopher D Cox 1,  Peter S Kutchukian 1,  David A Powell 1,  Corey Strickland 2,  B Wesley Trotter 3,  Matthew Tudor 1,  Scott Wolkenberg 1,  Jing Li 1,  David M Tellers 1
Affiliations

Affiliations

  • 1 MRL, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 2 MRL, Merck & Co., Inc., Kenilworth, New Jersey, 07033, United States.
  • 3 MRL, Merck & Co., Inc., Boston, Massachusetts, 02115, United States.
PMID: 33488970 DOI: 10.1021/acsmedchemlett.0c00551
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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