| Autor: |
Hwang, Dong-Jin, He, Yali, Ponnusamy, Suriyan, Mohler, Michael L., Thiyagarajan, Thirumagal, McEwan, Iain J., Narayanan, Ramesh, Miller, Duane D. |
| Zdroj: |
Journal of Medicinal Chemistry; December 2018, Vol. 62 Issue: 2 p491-511, 21p |
| Abstrakt: |
In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series IIand III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to IIand IIIproduced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). IIand IIImaintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration-resistant, Enz-R, and/or AR SV-dependent advanced PCs that are often untreatable with known hormone therapies are discussed. |
| Databáze: |
Supplemental Index |
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