Discovery of Novel Bicyclic Phenylselenyl-Containing Hybrids: An Orally Bioavailable, Potential, and Multiacting Class of Estrogen Receptor Modulators against Endocrine-Resistant Breast Cancer,Journal of Medicinal Chemistry

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Discovery of Novel Bicyclic Phenylselenyl-Containing Hybrids: An Orally Bioavailable, Potential, and Multiacting Class of Estrogen Receptor Modulators against Endocrine-Resistant Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-24 , DOI: 10.1021/acs.jmedchem.2c00525
Xiangping Deng ₁ , Baohua Xie ₂ , Qiuzi Li ₁ , Yuan Xiao ₂ , Zhiye Hu ₂ , Xiaofei Deng ₂ , Pingping Fang ₃ , Chune Dong ₂ , Hai-Bing Zhou ₂ , Jian Huang ₁

Affiliation

Breast cancer (BC) is a multifactorial disease and is prone to drug resistance during treatment. In this study, we described a new class of multifunctional estrogen receptor (ER) modulators ground on a prerogative indirect antagonism skeleton (OBHS, oxabicycloheptene sulfonate) of ER containing a phenylselenyl group. Compound 34b showed significant antiproliferative activities against tamoxifen-sensitive (MCF-7) and -resistant (LCC2) cells. Moreover, hexokinase 1 (HK1) was identified as a direct target of 34b. Further mechanism investigations proved that 34b induced apoptosis, which was associated with mitochondrial dysfunction caused by the synergistic effects of downregulating mitochondrial-bound HK1 protein and promoting reactive oxygen species generation. In vivo, 34b had a favorable pharmacokinetic profile with a bioavailability of 23.20% and exhibited more potent tumor suppression than tamoxifen both in MCF-7 and LCC2 tumor xenograft models. Collectively, our studies showed that 34b is a promising new multifunctional candidate compound for ERα⁺ BC treatment, particularly for tamoxifen-resistant BC.

中文翻译：

发现新的含双环苯基硒基的杂化物：一种口服生物可利用的、潜在的和多作用的雌激素受体调节剂，可对抗内分泌抗性乳腺癌

乳腺癌（BC）是一种多因素疾病，在治疗过程中容易产生耐药性。在这项研究中，我们描述了一类新的多功能雌激素受体 (ER) 调节剂，该调节剂基于含有苯硒基的 ER 的特权间接拮抗骨架（OBHS，氧杂二环庚烯磺酸盐）。化合物34b对他莫昔芬敏感 (MCF-7) 和耐药 (LCC2) 细胞显示出显着的抗增殖活性。此外，己糖激酶 1 (HK1) 被确定为34b的直接靶标。进一步的机制研究证明，34b诱导细胞凋亡，这与由下调线粒体结合的 HK1 蛋白和促进活性氧生成的协同作用引起的线粒体功能障碍有关。在体内，34b具有良好的药代动力学特征，生物利用度为 23.20%，并且在 MCF-7 和 LCC2 肿瘤异种移植模型中表现出比他莫昔芬更有效的肿瘤抑制作用。总的来说，我们的研究表明，34b是一种很有前途的新型多功能候选化合物，用于 ERα ⁺ BC 治疗，特别是对于他莫昔芬耐药的 BC。

更新日期：2022-05-24

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