Abstract
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
Keywords:
Breast cancer; Degrader; Estrogen receptor; SERD; Tamoxifen-resistant.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cinnamates / chemical synthesis
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Cinnamates / chemistry
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Cinnamates / pharmacology*
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects*
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Drug Screening Assays, Antitumor
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Female
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Indazoles / chemical synthesis
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Indazoles / chemistry
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Indazoles / pharmacology*
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Molecular Structure
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Receptors, Estrogen / antagonists & inhibitors*
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Receptors, Estrogen / metabolism
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Selective Estrogen Receptor Modulators / chemical synthesis
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Selective Estrogen Receptor Modulators / chemistry
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Selective Estrogen Receptor Modulators / pharmacology*
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Structure-Activity Relationship
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Tamoxifen / chemical synthesis
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Tamoxifen / chemistry
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Tamoxifen / pharmacology*
Substances
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3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
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Antineoplastic Agents
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Cinnamates
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Indazoles
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Receptors, Estrogen
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Selective Estrogen Receptor Modulators
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Tamoxifen