TY - JOUR
T1 - Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer
AU - Xiong, Rui
AU - Zhao, Jiong
AU - Gutgesell, Lauren M.
AU - Wang, Yueting
AU - Lee, Sue
AU - Karumudi, Bhargava
AU - Zhao, Huiping
AU - Lu, Yunlong
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
N1 - Funding Information:
This work was supported by NIH R01 CA188017, the University of Illinois Cancer Center, UICentre (drug discovery@UIC), and UIC Center for Clinical and Translational Science grant UL1RR029879. We would like to thank Kathryn Carlson and Teresa Martin for technical assistance with the RBA assay and John A. Katzenellenbogen for helpful comments, all from the Department of Chemistry, University of Illinois at Urbana− Champaign.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/2/23
Y1 - 2017/2/23
N2 - 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 ERα 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.
AB - 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 ERα 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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U2 - 10.1021/acs.jmedchem.6b01355
DO - 10.1021/acs.jmedchem.6b01355
M3 - Article
C2 - 28117994
AN - SCOPUS:85013863131
SN - 0022-2623
VL - 60
SP - 1325
EP - 1342
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -