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

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

doi:10.1016/j.bmcl.2015.09.074

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. Epub 2015 Oct 3.

Authors

Steven P Govek¹, Johnny Y Nagasawa², Karensa L Douglas², Andiliy G Lai², Mehmet Kahraman², Celine Bonnefous², Anna M Aparicio², Beatrice D Darimont², Katherine L Grillot², James D Joseph², Joshua A Kaufman², Kyoung-Jin Lee², Nhin Lu², Michael J Moon², Rene Y Prudente², John Sensintaffar², Peter J Rix², Jeffrey H Hager², Nicholas D Smith²

Affiliations

¹ Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States. Electronic address: [email protected].
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.

MeSH terms

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

Substances

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