Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 11, Pages 7993-8010Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00525
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Funding
- National Key R&D Program of China [2020YFA0908800]
- NSFC [82073690, 81773557, 82173676, 81573279, 31870786]
- Fundamental Research Funds for the Central Universities of China [2042021kf1033]
- Seed Funds for International Joint Research Platform of Wuhan University [KYPT-ZD-9]
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This study identified a new ER modulator, 34b, which showed antiproliferative effects against breast cancer cells and induced apoptosis through mitochondrial dysfunction. In vivo experiments demonstrated that 34b had better tumor suppression than tamoxifen. Therefore, this compound has potential as a candidate for treating breast cancer, particularly tamoxifen-resistant breast cancer.
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 ER alpha(+) BC treatment, particularly for tamoxifen-resistant BC.
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