title: The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
abstract: ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Joseph
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Darimont
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Arrazate
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Young
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ingalla
authors.affiliation: Department of Oncology Biomarker Development, Genentech, South San Francisco, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walter
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Blake
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Departments of Discovery Oncology and Early Discovery Biochemistry, Genentech, South San Francisco, United States.
authors.forename: Lorna
authors.initials: L
authors.lastname: Kategaya
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Govek
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Andiliy G
authors.initials: AG
authors.lastname: Lai
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kahraman
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Brigham
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sensintaffar
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Nhin
authors.initials: N
authors.lastname: Lu
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Shao
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Kate
authors.initials: K
authors.lastname: Grillot
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Rene
authors.initials: R
authors.lastname: Prudente
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Bischoff
authors.affiliation: Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Celine
authors.initials: C
authors.lastname: Bonnefous
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Karensa L
authors.initials: KL
authors.lastname: Douglas
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Jackaline D
authors.initials: JD
authors.lastname: Julien
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Johnny Y
authors.initials: JY
authors.lastname: Nagasawa
authors.affiliation: Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Aparicio
authors.affiliation: Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Josh
authors.initials: J
authors.lastname: Kaufman
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Department of Pathology, Genentech, South San Francisco, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Giltnane
authors.affiliation: Departments of Discovery Oncology and Early Discovery Biochemistry, Genentech, South San Francisco, United States.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Wertz
authors.affiliation: Department of Oncology Biomarker Development, Genentech, South San Francisco, United States.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Nannini
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Schwarz
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, United States.
authors.forename: Henry Charles
authors.initials: HC
authors.lastname: Manning
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, United States.
authors.forename: Mohammed Noor
authors.initials: MN
authors.lastname: Tantawy
authors.affiliation: Department of Medicine and Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, United States.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
authors.affiliation: Department of Drug Safety and Disposition, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rix
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.affiliation: Department of Chemistry, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, United States.
authors.forename: Ciara
authors.identifier: http://orcid.org/0000-0001-7233-661X
authors.initials: C
authors.lastname: Metcalfe
authors.affiliation: Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D051379:Mice; D011446:Prospective Studies; D051381:Rats; D011960:Receptors, Estrogen / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C000606997:3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D007191:Indazoles; D011960:Receptors, Estrogen
keywords: GDC-0810; SERD; breast cancer; cancer biology; estrogen receptor; human; human biology; medicine