IngentaConnect Cell line-directed screening assay for inhibitors of thioredoxin ...

Authors: Kunkel M.; Kirkpatrick D.¹; Johnson J.²; Powis G.³

Source: Anti-Cancer Drug Design, Volume 12, Number 8, 1997 , pp. 659-670(12)

Publisher: Cognizant Communication Corporation

Abstract:

We have used a cell line-directed screening approach (CDSA) to identify novel inhibitors of the thioredoxin reductase signaling pathway which contributes to the transformed phenotype of some human tumors. Two 2-imidazolyl disulfide compounds, previously identified as inhibitors of thioredoxin reductase, were screened for growth inhibitory activity in the National Cancer Institute (NCI) human cancer cell line panel. The COMPARE pattern recognition algorithm was used to identify similar compounds from >60 000 compounds in the NCI investigational drug database. Of 47 nondiscreet compounds tested in a thioredoxin reductase/thioredoxin insulin reduction assay, 27 (77%) were inhibitors with IC₅₀s

g/ml and 15 of those (32%) had IC₅₀s

g/ml. These compounds were all as selective or more selective for thioredoxin reductase than for glutathione reductase, while three compounds were inhibitors of thioredoxin. In comparison to CDSA, the number of compounds with IC₅₀s

g/ml identified by screening of 52 compounds from the database whose growth inhibiting activity was unrelated to the activity of the disulfide compounds was only 2%. Screening of 221 randomly selected natural products gave only 3% of compounds with IC₅₀s

g/ml. Thus, the CDSA using data from the NCI cancer cell panel and known inhibitors of the selected target as seed compounds can greatly increase hit rates, compared with random screening, for identifying novel inhibitors of a target, in this case thioredoxin signaling.

Key words: cancer/COMPARE/screening/thioredoxin/thioredoxin reductase

Document Type: Research article

Affiliations: 1: Department of Chemistry, University of Regina, Regina, Saskatchewan S4S 0A2, Canada 2: National Cancer Institute, National Institutes of Health, Division of Cancer Treatment, Developmental Therapeutics Program, Bethesda, MD 20892, USA 3: Corresponding author at: Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA

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Cell line-directed screening assay for inhibitors of thioredoxin reductase signaling as potential anti-cancer drugs