Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3
| Autor: | Timothy Palzkill, Jianming Xu, Chengwei Zhang, Jin Wang, David M. Lonard, Xianzhou Song, Dar Chone Chow, Yang Yu, Bert W. O'Malley, Jianwei Chen, Mingkun Zhao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Transcription Genetic Cell hERG Breast Neoplasms Biology Pharmacology Nuclear Receptor Coactivator 3 03 medical and health sciences Mice Cell Line Tumor Coactivator medicine Animals Humans Nuclear protein Receptor Multidisciplinary Hydrazones Biological Sciences Small molecule 030104 developmental biology medicine.anatomical_structure Drug development Nuclear receptor coactivator 3 biology.protein Benzimidazoles Female Protein Processing Post-Translational |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 113(18) |
| ISSN: | 1091-6490 |
| Popis: | Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators. |
| Databáze: | OpenAIRE |
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