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.
Bibliographical noteFunding Information:
This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics ( 73-01 to M.A.W. and Z.Z.), the NIH ( GM72719 and GM81838 to Z.Z.), the Mayo Foundation for Medical Education and Research and the Minnesota Supercomputing Institute. J.L.D. was supported by an NIH predoctoral fellowship (F30 DK092026-01), a Pharmaceutical Research and Manufacturers of America Foundation predoctoral pharmacology/toxicology fellowship and the Mayo Foundation. Funding for NMR instrumentation was provided by the Office of the Vice President for Research, the University of Minnesota Medical School, the University of Minnesota College of Biological Science, the NIH, the NSF and the Minnesota Medical Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the funders.
© 2015 Elsevier Ltd. All rights reserved.
- Chemical aggregation
- Drug discovery
- High-throughput screening
- Pan-assay interference compounds
- Structureactivity relationships