Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 5, Pages 2091-2113Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5019093
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Funding
- Minnesota Partnership for Biotechnology and Medical Genomics [73-01]
- NIH [GM72719, GM81838, F30 DK092026-01]
- Mayo Foundation for Medical Education and Research
- Minnesota Supercomputing Institute
- Pharmaceutical Research and Manufacturers of America Foundation
- Mayo Foundation
- Office of the Vice President for Research
- University of Minnesota Medical School
- University of Minnesota College of Biological Science
- NSF
- Minnesota Medical Foundation
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Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compounds, while understanding the chemical basis for these adverse behaviors often goes unexplored in pursuit of lead compounds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compounds. Herein, we characterize the chemical basis for assay interference and promiscuous enzymatic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compounds (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compounds react covalently with cysteines on multiple proteins. Unfortunately, compounds containing these chemotypes have been published as screening actives in reputable journals and even touted as chemical probes or preclinical candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compounds, guide screening library design, and prevent follow-up on undesirable chemical matter.
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