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

卷:25

Article

Dahlin, Jayme L.^1,2  Nissink, J. Willem M.³  Francis, Subhashree⁴  Strasser, Jessica M.⁴  John, Kristen⁴  Zhang, Zhiguo⁵  Walters, Michael A.⁴ 

[1] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Coll Med, Rochester, MN 55905 USA

[2] Mayo Clin, Coll Med, Med Scientist Training Program, Rochester, MN 55905 USA

[3] AstraZeneca, Oncol Innovat Med, Cambridge CB4 0WG, England

[4] Univ Minnesota, Inst Therapeut Discovery & Dev, Minneapolis, MN 55414 USA

[5] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA

关键词: Chemical aggregation;    Drug discovery;    High-throughput screening;    Pan-assay interference compounds;    PAINS;    Structure-activity relationships;   

DOI  :  10.1016/j.bmcl.2015.08.020

来源: Elsevier

【 摘 要 】

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 beta-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. (C) 2015 Elsevier Ltd. All rights reserved.

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