dc.contributor.author |
Zhang, Yan |
|
dc.contributor.author |
Wu, Xishan |
|
dc.contributor.author |
Xue, Xiaoqian |
|
dc.contributor.author |
Li, Chenchang |
|
dc.contributor.author |
Wang, Junjian |
|
dc.contributor.author |
Wang, Rui |
|
dc.contributor.author |
Zhang, Cheng |
|
dc.contributor.author |
Wang, Chao |
|
dc.contributor.author |
Shi, Yudan |
|
dc.contributor.author |
Zou, Lingjiao |
|
dc.contributor.author |
Li, Qiu |
|
dc.contributor.author |
Huang, Zenghong |
|
dc.contributor.author |
Hao, Xiaojuan |
|
dc.contributor.author |
Loomes, Kerry |
|
dc.contributor.author |
Wu, Donghai |
|
dc.contributor.author |
Chen, Hong-Wu |
|
dc.contributor.author |
Xu, Jinxin |
|
dc.contributor.author |
Xu, Yong |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2022-06-10T04:35:13Z |
|
dc.date.available |
2022-06-10T04:35:13Z |
|
dc.date.issued |
2019-05 |
|
dc.identifier.citation |
(2019). Journal of Medicinal Chemistry, 62(9), 4716-4730. |
|
dc.identifier.issn |
0022-2623 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/59722 |
|
dc.description.abstract |
We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC<sub>50</sub> value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
American Chemical Society (ACS) |
|
dc.relation.ispartofseries |
Journal of medicinal chemistry |
|
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.subject |
Microsomes, Liver |
|
dc.subject |
Animals |
|
dc.subject |
Mice |
|
dc.subject |
Rats |
|
dc.subject |
Acetanilides |
|
dc.subject |
Sulfonamides |
|
dc.subject |
Antineoplastic Agents |
|
dc.subject |
Xenograft Model Antitumor Assays |
|
dc.subject |
Cell Proliferation |
|
dc.subject |
Gene Expression |
|
dc.subject |
Binding Sites |
|
dc.subject |
Molecular Structure |
|
dc.subject |
Protein Binding |
|
dc.subject |
Structure-Activity Relationship |
|
dc.subject |
Drug Design |
|
dc.subject |
Male |
|
dc.subject |
Drug Inverse Agonism |
|
dc.subject |
Nuclear Receptor Subfamily 1, Group F, Member 3 |
|
dc.subject |
Molecular Docking Simulation |
|
dc.subject |
Prostatic Neoplasms, Castration-Resistant |
|
dc.subject |
Biotechnology |
|
dc.subject |
Prostate Cancer |
|
dc.subject |
Urologic Diseases |
|
dc.subject |
Cancer |
|
dc.subject |
5.1 Pharmaceuticals |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Chemistry, Medicinal |
|
dc.subject |
Pharmacology & Pharmacy |
|
dc.subject |
ABIRATERONE ACETATE |
|
dc.subject |
INCREASED SURVIVAL |
|
dc.subject |
DERIVATIVES |
|
dc.subject |
ENZALUTAMIDE |
|
dc.subject |
OPTIMIZATION |
|
dc.subject |
INHIBITORS |
|
dc.subject |
T0901317 |
|
dc.subject |
IDENTIFICATION |
|
dc.subject |
AMIDES |
|
dc.subject |
1112 Oncology and Carcinogenesis |
|
dc.subject |
Biomedical |
|
dc.subject |
Basic Science |
|
dc.subject |
Aging |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1021/acs.jmedchem.9b00327 |
|
pubs.issue |
9 |
|
pubs.begin-page |
4716 |
|
pubs.volume |
62 |
|
dc.date.updated |
2022-05-02T06:23:21Z |
|
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
30964293 (pubmed) |
|
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/30964293 |
|
pubs.end-page |
4730 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
Research Support, U.S. Gov't, Non-P.H.S. |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
772774 |
|
pubs.org-id |
Science |
|
pubs.org-id |
Biological Sciences |
|
pubs.org-id |
Science Research |
|
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
|
dc.identifier.eissn |
1520-4804 |
|
pubs.record-created-at-source-date |
2022-05-02 |
|
pubs.online-publication-date |
2019-04-09 |
|