TY - JOUR
T1 - Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer
AU - Lu, Yunlong
AU - Gutgesell, Lauren M.
AU - Xiong, Rui
AU - Zhao, Jiong
AU - Li, Yangfeng
AU - Rosales, Carlo I.
AU - Hollas, Michael
AU - Shen, Zhengnan
AU - Gordon-Blake, Jesse
AU - Dye, Katherine
AU - Wang, Yueting
AU - Lee, Sue
AU - Chen, Hu
AU - He, Donghong
AU - Dubrovyskyii, Oleksii
AU - Zhao, Huiping
AU - Huang, Fei
AU - Lasek, Amy W.
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
AB - The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
UR - http://www.scopus.com/inward/record.url?scp=85076818486&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076818486&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01580
DO - 10.1021/acs.jmedchem.9b01580
M3 - Article
C2 - 31746603
AN - SCOPUS:85076818486
SN - 0022-2623
VL - 62
SP - 11301
EP - 11323
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -