Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):367-372. doi: 10.1016/j.bmcl.2018.12.042.
Steven P Govek  1 ,  Celine Bonnefous  2 ,  Jackaline D Julien  2 ,  Johnny Y Nagasawa  2 ,  Mehmet Kahraman  2 ,  Andiliy G Lai  2 ,  Karensa L Douglas  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: [email protected].
  • 2. Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
PMID: 30587451 DOI: 10.1016/j.bmcl.2018.12.042
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.