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.
Original language | English (US) |
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Pages (from-to) | 4740-4752 |
Number of pages | 13 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 25 |
Issue number | 21 |
DOIs | |
State | Published - Nov 1 2015 |
Keywords
- Chemical aggregation
- Drug discovery
- High-throughput screening
- PAINS
- Pan-assay interference compounds
- Structureactivity relationships
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry