Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Eur J Med Chem. 2024 Dec 5;279:116897. doi: 10.1016/j.ejmech.2024.116897. Epub 2024 Sep 21.
Elacestrant, the first oral selective estrogen receptor degrader (SERD), has been approved for ER positive breast cancer in 2023. Recent study showed that elacestrant has moderate pharmacokinetic property and the oral bioavailability is 11 %. In this study, we have performed docking analyses of elacestrant with different cytochrome P450 isoforms. The results indicated that tetrahydronaphthalene scaffold of elacestrant located closely to Heme iron center of P450s and might undergo rapid metabolism by CYP3A4. Therefore, we have changed the tertiary carbon atom to nitrogen atom of the scaffold to attenuate the metabolic effect. The most interesting finding is that compound B16 exhibited significant degradation of ERα at 5 μM but didn't show antiproliferative activity at high concentrations in MCF-7 and T47D cells. Compound B16 may serve as an ER probe to investigate ER status in ER positive breast cancer cells.
Elacestrant 是首个获批用于治疗雌激素受体阳性乳腺癌的口服选择性雌激素受体降解剂（SERD）。最近的研究表明，Elacestrant 具有中等的药代动力学特性，口服生物利用度为 11%。在这项研究中，我们对 Elacestrant 与不同细胞色素 P450 同工酶进行了对接分析。结果表明，Elacestrant 的四氢萘骨架与 P450 中的血红素铁中心紧密结合，可能会被 CYP3A4 快速代谢。因此，我们将支架上的叔碳原子改为氮原子，以减弱代谢作用。最有趣的发现是，化合物 B16 在 5 μM 时显著降解 ERα，但在 MCF-7 和 T47D 细胞中高浓度时没有表现出抗增殖活性。化合物 B16 可作为 ER 探针，用于研究 ER 阳性乳腺癌细胞中的 ER 状态。
