Post-HTS case report and structural alert: Promiscuous 4-aroyl-1, 5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Dahlin, Jayme L.; Nissink, J. Willem M.; Francis, Subhashree; Strasser, Jessica M.; John, Kristen; Zhang, Zhiguo; Walters, Michael A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 21(2015)
• Page Start: 4740
• Page End: 4752
• Publication Date: 2015-11-01
• Subjects: acetyl-CoA acetyl coenzyme A -- ALARM NMR a La assay to detect reactive molecules by nuclear magnetic resonance -- Asf1 anti-silencing function 1 -- AZ AstraZeneca -- BME β-mercaptoethanol -- BSA bovine serum albumin -- CoA coenzyme A -- CPM N-[4-(7-diethylamino-4-methylcoumarin-3-yl)phenyl]maleimide -- dH3–H4 Drosophila histone H3–H4 -- DMSO dimethyl sulfoxide -- DNA deoxyribonucleic acid -- DTT dithiothreitol -- EDTA ethylenediaminetetraacetic acid -- GSH Glutathione -- H3K9 histone H3 lysine 9 -- H3K27 histone H3 lysine 27 -- H3K56 histone H3 lysine 56 -- H3K56ac histone H3 lysine 56 acetylation -- HAT histone acetyltransferase -- HMQC heteronuclear multiple quantum coherence -- HPLC high-performance liquid chromatography -- HRMS high-resolution mass spectrometry -- HRP-PR horseradish peroxidase-phenol red -- HTS high-throughput screen or high-throughput screening -- IC50 half maximal inhibitory concentration -- IPTG isopropyl β-d-1-thiogalactopyranoside -- log D distribution coefficient -- log P partition coefficient -- m/z mass-to-charge ratio -- LRMS-ESI low-resolution mass spectrometry–electrospray ionization -- MeCN acetonitrile -- MeOH methanol -- MS mass spectrometry -- NMR nuclear magnetic resonance -- PAINS pan-assay interference compounds -- pBSF negative log of binomial survivor function -- REOS Rapid Elimination Of Swill -- Rtt109 regulator of Ty1 transposition 109 -- SAR structure–activity relationship -- SDS–PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis -- SIR structure–interference relationship -- TFA trifluoroacetic acid -- UPLC ultra-performance liquid chromatography -- Vps75 vacuolar protein sorting 75; Chemical aggregation -- Drug discovery -- High-throughput screening -- Pan-assay interference compounds -- PAINS -- Structure–activity relationships; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.020
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Despite its wide use, not every high-throughput screen (HTS) yields chemical matter suitable for drug development campaigns, and seldom are 'go/no-go' decisions in drug discovery described in detail. This case report describes the follow-up of a 4-aroyl-1, 5-disubstituted-3-hydroxy-2 H -pyrrol-2-one active from a cell-free HTS to identify small-molecule inhibitors of Rtt109-catalyzed histone acetylation. While this compound and structural analogs inhibited Rtt109-catalyzed histone acetylation in vitro, further work on this series was halted after several risk mitigation strategies were performed. Compounds with this chemotype had a poor structure–activity relationship, exhibited poor selectivity among other histone acetyltransferases, and tested positive in a β-lactamase counter-screen for chemical aggregates. Furthermore, ALARM NMR demonstrated compounds with this chemotype grossly perturbed the conformation of the La protein. In retrospect, this chemotype was flagged as a 'frequent hitter' in an analysis of a large corporate screening deck, yet similar compounds have been published as screening actives or chemical probes versus unrelated biological targets. This report—including the decision-making process behind the 'no-go' decision—should be informative for groups engaged in post-HTS triage and highlight the importance of considering physicochemical properties in early drug discovery.