Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

Rui Xiong, Jiong Zhao, Lauren M. Gutgesell, Yueting Wang, Sue Lee, Bhargava Karumudi, Huiping Zhao, Yunlong Lu, Debra A. Tonetti, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1325-1342
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 23 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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