5 research outputs found
Identification of an imidazopyridine-based compound as an oral selective estrogen receptor degrader for breast cancer therapy
Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-Ī± in Hormone-Resistant Breast Cancers
Estrogen receptor-Ī± positive (ERĪ±+) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERĪ± and promotes constitutive activation of ERĪ± function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERĪ± represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. A systematic computer-guided drug discovery approach was employed to develop a potent ERĪ± inhibitor that was extensively evaluated by a series of experiments to confirm its AF2-specific activity. We demonstrate that the developed small-molecule inhibitor effectively prevents ERĪ±-coactivator interactions and exhibits a strong anti-proliferative effect against tamoxifen-resistant cells, as well as downregulates ERĪ±-dependent genes and effectively diminishes the receptor binding to chromatin. Notably, the identified lead compound successfully inhibits known constitutively-active, resistance-associated mutant forms of ERĪ± observed in clinical settings. Overall, this study reports the development of a novel class of ERĪ± AF2 inhibitors, which have the potential to effectively inhibit ERĪ± activity by a unique mechanism and to circumvent the issue of mutation-driven resistance in breast cancer.Other UBCReviewedFacult
Discovery of 1<i>H</i>āIndole-2-carboxamides as Novel Inhibitors of the Androgen Receptor Binding Function 3 (BF3)
To overcome resistance to conventional
anti-androgens of human
androgen receptor (AR), the allosteric site of the AR binding function
3 (BF3) was investigated as an alternative target for small molecule
therapeutics. A library of 1<i>H-</i>indole-2-carboxamides
were discovered as BF3 inhibitors and exhibited strong antiproliferative
activity against LNCaP and enzalutamide-resistant prostate cancer
cell lines. Several of the lead compounds may prove of particular
benefit as a novel alternative treatment for castration-resistant
prostate cancers