Fan, Fan and Hu, Rong and Munzli, Anke and Chen, Yuan and Dunn, Robert T. and Weikl, Kerstin and Strauch, Simone and Schwandner, Ralf and Afshari, Cynthia A. and Hamadeh, Hisham and Nioi, Paul (2015) Utilization of Human Nuclear Receptors as an Early Counter Screen for Off-Target Activity: A Case Study with a Compendium of 615 Known Drugs. TOXICOLOGICAL SCIENCES, 145 (2). pp. 283-295. ISSN 1096-6080, 1096-0929
Full text not available from this repository. (Request a copy)Abstract
Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen alpha/beta, and thyroid hormone alpha/beta receptors. Our study revealed that 4.7 and 12.4% compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/development.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROSTATE-CANCER; ANDROGEN-RECEPTOR; ESTROGEN-RECEPTOR; IN-VIVO; SUPERFAMILY; PHARMACOKINETICS; ACTIVATION; THERAPY; BETAMETHASONE; ANTIANDROGENS; nuclear hormone receptor; in vitro; profiling; androgen receptor; progesterone receptor; estrogen receptor; thyroid receptor; hazard identification |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jul 2019 08:04 |
| Last Modified: | 15 Jul 2019 08:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5430 |
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