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

Bioorganic & Medicinal Chemistry Letters
Jayme L DahlinMichael A Walters

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' dec...Continue Reading

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Citations

Dec 15, 2015·Expert Opinion on Drug Discovery·Martin Klumpp
Jan 4, 2017·ACS Chemical Biology·Jose M ArencibiaRicardo M Biondi
Jun 29, 2017·Journal of Medicinal Chemistry·Anamarija Zega
Nov 17, 2017·Nature Communications·Jayme L DahlinMichael A Walters
Aug 23, 2019·Medicinal Research Reviews·Catherine H Schein
Jul 24, 2018·Current Protocols in Chemical Biology·Jayme L DahlinMichael A Walters
Mar 7, 2020·Scientific Reports·Alexandre BorrelNicole C Kleinstreuer
Jun 12, 2021·SLAS Discovery·Kathryn M Nelson, Michael A Walters
Oct 20, 2017·Journal of Chemical Information and Modeling·Peter W Kenny

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