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: Steven P Govek, Johnny Y Nagasawa, Karensa L Douglas, Andiliy G Lai, Mehmet Kahraman, Celine Bonnefous, Anna M Aparicio, Beatrice D Darimont, Katherine L Grillot, James D Joseph, Joshua A Kaufman, Kyoung-Jin Lee, Nhin Lu, Michael J Moon, Rene Y Prudente, John Sensintaffar, Peter J Rix, Jeffrey H Hager, Nicholas D Smith
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 22 Pg. 5163-7 (Nov 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26463130 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• 3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
• Antineoplastic Agents
• Cinnamates
• Estrogen Receptor Antagonists
• Indazoles
• Tamoxifen

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cinnamates (therapeutic use)
• Drug Resistance, Neoplasm
• Estrogen Receptor Antagonists (metabolism, therapeutic use)
• Female
• Indazoles (chemistry, therapeutic use)
• Rats
• Structure-Activity Relationship
• Tamoxifen (therapeutic use)
• Xenograft Model Antitumor Assays