Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility.

Autor:	Guan J; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Zhou W; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Hafner M; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Blake RA; Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA., Chalouni C; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Chen IP; Department of Medicine, UCSF, San Francisco, CA 94143, USA., De Bruyn T; Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA., Giltnane JM; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Hartman SJ; Theravance Biopharma, South San Francisco, CA 94080, USA., Heidersbach A; Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA., Houtman R; Department of Research and Development, PamGene, 5211 HH's-Hertogenbosch, the Netherlands., Ingalla E; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Kategaya L; Ideaya Biosciences, South San Francisco, CA 94080, USA., Kleinheinz T; Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA., Li J; Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA., Martin SE; Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA., Modrusan Z; Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA., Nannini M; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Oeh J; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Ubhayakar S; Department of Medicine, UCSF, San Francisco, CA 94143, USA., Wang X; Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA., Wertz IE; Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA., Young A; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Yu M; Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA., Sampath D; Department of Research, Ultragenyx, Novato, CA 94949, USA., Hager JH; Ideaya Biosciences, South San Francisco, CA 94080, USA., Friedman LS; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA., Daemen A; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Metcalfe C; Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA. Electronic address: metcalfe.ciara@gene.com.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2019 Aug 08; Vol. 178 (4), pp. 949-963.e18. Date of Electronic Publication: 2019 Jul 25.
DOI:	10.1016/j.cell.2019.06.026
Abstrakt:	Estrogen receptor-positive (ER + ) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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