Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer

Rui Xiong; Hitisha K. Patel; Lauren M. Gutgesell; Jiong Zhao; Loruhama Delgado-Rivera; Thao N.D. Pham; Huiping Zhao; Kathryn Carlson; Teresa Martin; John A. Katzenellenbogen; Terry W. Moore; Debra A. Tonetti; Gregory R.J. Thatcher

doi:10.1021/acs.jmedchem.5b01276

Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer

Rui Xiong, Hitisha K. Patel, Lauren M. Gutgesell, Jiong Zhao, Loruhama Delgado-Rivera, Thao N.D. Pham, Huiping Zhao, Kathryn Carlson, Teresa Martin, John A. Katzenellenbogen, Terry W. Moore, Debra A. Tonetti, Gregory R.J. Thatcher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	219-237
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01276
State	Published - Jan 14 2016
Externally published	Yes

Funding

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.

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.jmedchem.5b01276

Cite this

Xiong, R., Patel, H. K., Gutgesell, L. M., Zhao, J., Delgado-Rivera, L., Pham, T. N. D., Zhao, H., Carlson, K., Martin, T., Katzenellenbogen, J. A., Moore, T. W., Tonetti, D. A., & Thatcher, G. R. J. (2016). Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer. Journal of Medicinal Chemistry, 59(1), 219-237. https://doi.org/10.1021/acs.jmedchem.5b01276

@article{3730de17584046f79e1e16392a5abdb0,

title = "Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer",

abstract = "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.",

author = "Rui Xiong and Patel, {Hitisha K.} and Gutgesell, {Lauren M.} and Jiong Zhao and Loruhama Delgado-Rivera and Pham, {Thao N.D.} and Huiping Zhao and Kathryn Carlson and Teresa Martin and Katzenellenbogen, {John A.} and Moore, {Terry W.} and Tonetti, {Debra A.} and Thatcher, {Gregory R.J.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2016",

month = jan,

day = "14",

doi = "10.1021/acs.jmedchem.5b01276",

language = "English (US)",

volume = "59",

pages = "219--237",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

}

Xiong, R, Patel, HK, Gutgesell, LM, Zhao, J, Delgado-Rivera, L, Pham, TND, Zhao, H, Carlson, K, Martin, T, Katzenellenbogen, JA, Moore, TW, Tonetti, DA & Thatcher, GRJ 2016, 'Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer', Journal of Medicinal Chemistry, vol. 59, no. 1, pp. 219-237. https://doi.org/10.1021/acs.jmedchem.5b01276

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84955261921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955261921&partnerID=8YFLogxK

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 -

Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this