title: Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Rui
authors.identifier: 0000-0002-6350-9037
authors.initials: R
authors.lastname: Xiong
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Gutgesell
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Sue
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Bhargava
authors.initials: B
authors.lastname: Karumudi
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Tonetti
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, ‡Department of Biopharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Gregory R J
authors.identifier: 0000-0002-7757-1739
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008819:Mice, Nude; D008958:Models, Molecular; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C088015:benzothiophene