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) |
|---|---|
| Pages (from-to) | 4740-4752 |
| Number of pages | 13 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 25 |
| Issue number | 21 |
| DOIs | |
| State | Published - Jun 2 2015 |
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Keywords
- Chemical aggregation
- Drug discovery
- High-throughput screening
- PAINS
- Pan-assay interference compounds
- Structureactivity relationships
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Molecular Biology
- Molecular Medicine
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Post-HTS case report and structural alert : Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR. / Dahlin, Jayme L.; Nissink, J. Willem M; Francis, Subhashree; Strasser, Jessica M.; John, Kristen; Zhang, Zhiguo; Walters, Michael A.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 21, 02.06.2015, p. 4740-4752.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Post-HTS case report and structural alert
T2 - Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR
AU - Dahlin, Jayme L.
AU - Nissink, J. Willem M
AU - Francis, Subhashree
AU - Strasser, Jessica M.
AU - John, Kristen
AU - Zhang, Zhiguo
AU - Walters, Michael A.
PY - 2015/6/2
Y1 - 2015/6/2
N2 - 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.
AB - 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.
KW - Chemical aggregation
KW - Drug discovery
KW - High-throughput screening
KW - PAINS
KW - Pan-assay interference compounds
KW - Structureactivity relationships
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UR - http://www.scopus.com/inward/citedby.url?scp=84944151490&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2015.08.020
DO - 10.1016/j.bmcl.2015.08.020
M3 - Article
VL - 25
SP - 4740
EP - 4752
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 21
ER -