title: Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.
abstract: Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States. Electronic address: sgovek@seragonpharm.com.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Govek
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Johnny Y
authors.initials: JY
authors.lastname: Nagasawa
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Karensa L
authors.initials: KL
authors.lastname: Douglas
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Andiliy G
authors.initials: AG
authors.lastname: Lai
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kahraman
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Celine
authors.initials: C
authors.lastname: Bonnefous
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Aparicio
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Beatrice D
authors.initials: BD
authors.lastname: Darimont
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Grillot
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Joseph
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kaufman
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Nhin
authors.initials: N
authors.lastname: Lu
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Moon
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Rene Y
authors.initials: RY
authors.lastname: Prudente
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sensintaffar
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rix
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
authors.affiliation: Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002934:Cinnamates / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D065171:Estrogen Receptor Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D007191:Indazoles / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
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; D065171:Estrogen Receptor Antagonists; D007191:Indazoles; D013629:Tamoxifen
keywords: Breast cancer; Degrader; Estrogen receptor; SERD; Tamoxifen-resistant