title: Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR.
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-2H-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.
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Jayme L
authors: JL
authors: Dahlin
authors: AstraZeneca, Oncology Innovative Medicines, Cambridge CB4 0WG, UK.
authors: J Willem M
authors: JWM
authors: Nissink
authors: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors: Subhashree
authors: S
authors: Francis
authors: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors: Jessica M
authors: JM
authors: Strasser
authors: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors: Kristen
authors: K
authors: John
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Zhiguo
authors: Z
authors: Zhang
authors: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA. Electronic address: mwalters@umn.edu.
authors: Michael A
authors: MA
authors: Walters
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000608287:3-hydroxy-2H-pyrrol-2-one; D011758:Pyrroles; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D051548:Histone Acetyltransferases; C517120:Rtt109 protein, S cerevisiae
keywords: Chemical aggregation; Drug discovery; High-throughput screening; PAINS; Pan-assay interference compounds; Structure–activity relationships