TY - JOUR
T1 - Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer
AU - Xiong, Rui
AU - Patel, Hitisha K.
AU - Gutgesell, Lauren M.
AU - Zhao, Jiong
AU - Delgado-Rivera, Loruhama
AU - Pham, Thao N.D.
AU - Zhao, Huiping
AU - Carlson, Kathryn
AU - Martin, Teresa
AU - Katzenellenbogen, John A.
AU - Moore, Terry W.
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
N1 - Funding Information:
This work was suppored by NIH Grants R01 CA188017 and R01 CA102590, the University of Illinois Cancer Center, UIC Center for Clinical and Translational Science Grant UL1RR029879. We also thank Dr. Bernard D. Santarsiero from the Center for Pharmaceutical Biotechnology and the Department of Medicinal Chemistry and Pharmacognosy at UIC for his help with X-ray crystallography experiments.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/1/14
Y1 - 2016/1/14
N2 - Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.
AB - Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.
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U2 - 10.1021/acs.jmedchem.5b01276
DO - 10.1021/acs.jmedchem.5b01276
M3 - Article
C2 - 26681208
AN - SCOPUS:84955261921
SN - 0022-2623
VL - 59
SP - 219
EP - 237
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -