Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5163-7. doi: 10.1016/j.bmcl.2015.09.074.

Steven P Govek ¹, Johnny Y Nagasawa ², Karensa L Douglas ², Andiliy G Lai ², Mehmet Kahraman ², Celine Bonnefous ², Anna M Aparicio ², Beatrice D Darimont ², Katherine L Grillot ², James D Joseph ², Joshua A Kaufman ², Kyoung-Jin Lee ², Nhin Lu ², Michael J Moon ², Rene Y Prudente ², John Sensintaffar ², Peter J Rix ², Jeffrey H Hager ², Nicholas D Smith ²

Affiliations

1 Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States. Electronic address: sgovek@seragonpharm.com.
2 Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.

PMID: 26463130 DOI: 10.1016/j.bmcl.2015.09.074

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.

Keywords

Breast cancer; Degrader; Estrogen receptor; SERD; Tamoxifen-resistant.

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