ArticleBioorganic & medicinal chemistry letters2015
Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR.
Article in Bioorganic & medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 17 citations in OpenAlex.
- Fragment screening targeting Ebola virus nucleoprotein C-terminal domain identifies lead candidates.Antiviral research · 2020Article
- Repurposing approved drugs on the pathway to novel therapies.Medicinal research reviews · 2020Review
- ALARM NMR for HTS triage and chemical probe validation.Current protocols in chemical biology · 2018Article
- Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors.Nature communications · 2017Article
- Towards a systematic assessment of assay interference: Identification of extensively tested compounds with high assay promiscuity.F1000Research · 2017Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
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.
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