Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer
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| Název: | Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer |
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| Autoři: | BRITISH COLUMBIA UNIV VANCOUVER, Cherkasov, Artem, Rennie, Paul |
| Zdroj: | DTIC |
| Informace o vydavateli: | 2014-10 |
| Druh dokumentu: | Electronic Resource |
| Abstrakt: | Interest in developing androgen receptor (AR) inhibitors with novel mechanism of action is slowly increasing since commercial anti-androgens (Bicalutamide, Flutamide, Nilutamide and Enzalutamide) face therapeutic limitations. Current therapies fail over a period of time because they all target hormone binding pocket on AR to which the receptor has already developed effective resistance mechanisms. One of the promising strategies to combat drug resistance is to develop the inhibitors that target an alternative binding pocket of the AR, called Binding Function 3 (BF3). In the current study, we report indole chemical series, identified through systematic in silico screen, as leading AR BF3 inhibitors. The most potent inhibitor (compound VPC-13566) demonstrated excellent anti-androgen potency, anti-PSA activity and abrogates androgen-induced proliferation of LNCaP and Enzalutamide-resistant prostate cancer cell lines. Moreover, it demonstrated clear reduction of tumour growth in tumor xenograft models in mice. Based on these results new derivatives have been developed to improve stability and better efficacy in in-vivo models. These findings provide evidence that targeting AR BF3 pocket using small molecule inhibitors is a viable therapeutic approach for patients with advanced prostate cancer. The original document contains color images. |
| Témata: | Biochemistry, Biology, Medicine and Medical Research, Pharmacology, ANDROGENS, DRUGS, PROSTATE CANCER, RESISTANCE(BIOLOGY), ASSAYING, CELLS(BIOLOGY), COMPUTER AIDED DESIGN, GENOMICS, INHIBITION, INHIBITORS, INTERFEROMETRY, MICROSOMES, MODELS, MOLECULES, NEOPLASMS, PROTEINS, RECEPTOR SITES(PHYSIOLOGY), SYNTHESIS(CHEMISTRY), TRANSCRIPTION(GENETICS), AR(ANDROGEN RECEPTORS), CHEMICAL GENOMICS, COMPUTER-AIDED DRUG DESIGN, DRUG RESISTANCE, HORMONE RESISTANCE, SMALL MOLECULE DRUGS, ANTI-ANDROGENS, BF3(BINDING FUNCTION 3), COMPOUND VPC-13566, PCA(PROSTATE CANCER), ENZALUTAMIDE RESISTANT CELLS, LNCAP CELLS, MTS ASSAYS, BLI(BIOLAYER INTERFEROMETRY), XENOGRAFT MODELS, Text |
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| Dostupnost: | Open access content. Open access content Approved for public release; distribution is unlimited. |
| Poznámka: | text/html English |
| Other Numbers: | DTICE ADA611450 913593876 |
| Přispívající zdroj: | From OAIster®, provided by the OCLC Cooperative. |
| Přístupové číslo: | edsoai.ocn913593876 |
| Databáze: | OAIster |
Nájsť tento článok vo Web of Science | Abstrakt: | Interest in developing androgen receptor (AR) inhibitors with novel mechanism of action is slowly increasing since commercial anti-androgens (Bicalutamide, Flutamide, Nilutamide and Enzalutamide) face therapeutic limitations. Current therapies fail over a period of time because they all target hormone binding pocket on AR to which the receptor has already developed effective resistance mechanisms. One of the promising strategies to combat drug resistance is to develop the inhibitors that target an alternative binding pocket of the AR, called Binding Function 3 (BF3). In the current study, we report indole chemical series, identified through systematic in silico screen, as leading AR BF3 inhibitors. The most potent inhibitor (compound VPC-13566) demonstrated excellent anti-androgen potency, anti-PSA activity and abrogates androgen-induced proliferation of LNCaP and Enzalutamide-resistant prostate cancer cell lines. Moreover, it demonstrated clear reduction of tumour growth in tumor xenograft models in mice. Based on these results new derivatives have been developed to improve stability and better efficacy in in-vivo models. These findings provide evidence that targeting AR BF3 pocket using small molecule inhibitors is a viable therapeutic approach for patients with advanced prostate cancer.<br />The original document contains color images. |
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