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Title: Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

Abstract

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404988
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Burks, Heather E., Abrams, Tinya, Kirby, Christina A., Baird, Jason, Fekete, Alexander, Hamann, Lawrence G., Kim, Sunkyu, Lombardo, Franco, Loo, Alice, Lubicka, Danuta, Macchi, Kaitlin, McDonnell, Donald P., Mishina, Yuji, Norris, John D., Nunez, Jill, Saran, Chitra, Sun, Yingchuan, Thomsen, Noel M., Wang, Chunrong, Wang, Jianling, and Peukert, Stefan. Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.6b01468.
Burks, Heather E., Abrams, Tinya, Kirby, Christina A., Baird, Jason, Fekete, Alexander, Hamann, Lawrence G., Kim, Sunkyu, Lombardo, Franco, Loo, Alice, Lubicka, Danuta, Macchi, Kaitlin, McDonnell, Donald P., Mishina, Yuji, Norris, John D., Nunez, Jill, Saran, Chitra, Sun, Yingchuan, Thomsen, Noel M., Wang, Chunrong, Wang, Jianling, & Peukert, Stefan. Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer. United States. doi:10.1021/acs.jmedchem.6b01468.
Burks, Heather E., Abrams, Tinya, Kirby, Christina A., Baird, Jason, Fekete, Alexander, Hamann, Lawrence G., Kim, Sunkyu, Lombardo, Franco, Loo, Alice, Lubicka, Danuta, Macchi, Kaitlin, McDonnell, Donald P., Mishina, Yuji, Norris, John D., Nunez, Jill, Saran, Chitra, Sun, Yingchuan, Thomsen, Noel M., Wang, Chunrong, Wang, Jianling, and Peukert, Stefan. Wed . "Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer". United States. doi:10.1021/acs.jmedchem.6b01468.
@article{osti_1404988,
title = {Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer},
author = {Burks, Heather E. and Abrams, Tinya and Kirby, Christina A. and Baird, Jason and Fekete, Alexander and Hamann, Lawrence G. and Kim, Sunkyu and Lombardo, Franco and Loo, Alice and Lubicka, Danuta and Macchi, Kaitlin and McDonnell, Donald P. and Mishina, Yuji and Norris, John D. and Nunez, Jill and Saran, Chitra and Sun, Yingchuan and Thomsen, Noel M. and Wang, Chunrong and Wang, Jianling and Peukert, Stefan},
abstractNote = {Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.},
doi = {10.1021/acs.jmedchem.6b01468},
journal = {Journal of Medicinal Chemistry},
number = 7,
volume = 60,
place = {United States},
year = {Wed Mar 15 00:00:00 EDT 2017},
month = {Wed Mar 15 00:00:00 EDT 2017}
}