Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR

Jayme L. Dahlin, J. Willem M Nissink, Subhashree Francis, Jessica M. Strasser, Kristen John, Zhiguo Zhang, Michael A. Walters

Research output: Contribution to journalArticle

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4740-4752
Number of pages13
JournalBioorganic and Medicinal Chemistry Letters
Issue number21
StatePublished - Jun 2 2015



  • Chemical aggregation
  • Drug discovery
  • High-throughput screening
  • Pan-assay interference compounds
  • Structureactivity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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