title: Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
abstract: Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Andiliy
authors: A
authors: Lai
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Mehmet
authors: M
authors: Kahraman
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Steven
authors: S
authors: Govek
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Johnny
authors: J
authors: Nagasawa
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Celine
authors: C
authors: Bonnefous
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Jackie
authors: J
authors: Julien
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Karensa
authors: K
authors: Douglas
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: John
authors: J
authors: Sensintaffar
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Nhin
authors: N
authors: Lu
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Kyoung-Jin
authors: KJ
authors: Lee
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Anna
authors: A
authors: Aparicio
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Josh
authors: J
authors: Kaufman
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Jing
authors: J
authors: Qian
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Gang
authors: G
authors: Shao
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Rene
authors: R
authors: Prudente
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Michael J
authors: MJ
authors: Moon
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: James D
authors: JD
authors: Joseph
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Beatrice
authors: B
authors: Darimont
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Daniel
authors: D
authors: Brigham
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Kate
authors: K
authors: Grillot
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Richard
authors: R
authors: Heyman
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Peter J
authors: PJ
authors: Rix
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Jeffrey H
authors: JH
authors: Hager
authors: †Department of Chemistry, ‡Department of Biology, §Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
authors: Nicholas D
authors: ND
authors: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / 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; D004285:Dogs; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D054852:Small Molecule Libraries; D013629:Tamoxifen