Year: 2023
Type: article
Abstract: Tricyclic tetrahydroquinolines (THQs) have been repeatedly reported as hits across a diverse range of high-throughput screening (HTS) campaigns. The activities of these compounds, however, are likely due to reactive byproducts that interfere with the assay. As a lesser studied class of pan-assay interference compounds, the mechanism by which fused THQs react with protein targets remains largely unknown. During HTS follow-up, we characterized the behavior and stability of several fused tricyclic THQs. We synthesized key analogues to pinpoint the cyclopentene ring double bond as a source of reactivity of fused THQs. We found that these compounds degrade in solution under standard laboratory conditions in days. Importantly, these observations make it likely that fused THQs, which are ubiquitously found within small molecule screening libraries, are unlikely the intact parent compounds. We urge deprioritization of tricylic THQ hits in HTS follow-up and caution against the investment of resources to follow-up on these problematic compounds.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Pfizer, Bayer, North Carolina Biotechnology Center, Emory University, McGill University, Genome Canada, Merck KGaA, Ontario Genomics, European Federation of Pharmaceutical Industries and Associations, Ontario Genomics Institute, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health, Genentech, National Institute on Aging, Eshelman Institute for Innovation, University of North Carolina at Chapel Hill
OpenAlex ID: W4387900688