期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 4, 页码 1325-1342出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01355
关键词
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资金
- NIH [R01 CA188017]
- University of Illinois Cancer Center, UICenter
- UIC Center for Clinical and Translational Science grant [UL1RR029879]
Resistance to the selective estrogen receptor modulator tamoxifen and to aromatase inhibitors that lower circulating estradiol occurs in up to 50% of patients, generally leading to an endocrine-independent ER+ phenotype. Selective ER downregulators (SERDs) are able to ablate ER and thus, theoretically, to prevent survival of both endocrine-dependent and -independent ER+ tumors. The clinical SERD fulvestrant is hampered by intramuscular administration and undesirable pharmacokinetics. Novel SERDs were designed using the 6-OH-benzothiophene (BT) scaffold common to arzoxifene and raloxifene. Treatment-resistant (TR) ER+ cell lines (MCF-7:5C and MCF-7:TAM1) were used for optimization, followed by validation in the parent endocrine-dependent cell line (MCF-7:WS8), in 2D and 3D cultures, using ER alpha in-cell westerns, ERE-luciferase, and cell viability assays, with 2 (GDC-0810/ARN-810) used for comparison. Two BT SERDs with superior in vitro activity to 2 were studied for bioavailability and shown to cause regression of a TR, endocrine -independent ER+ xenograft superior to that with 2.
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