The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer

Elife. 2016 Jul 13;5:e15828. doi: 10.7554/eLife.15828.

Abstract

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Keywords: GDC-0810; SERD; breast cancer; cancer biology; estrogen receptor; human; human biology; medicine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Cinnamates / administration & dosage*
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Indazoles / administration & dosage*
  • Mice
  • Prospective Studies
  • Rats
  • Receptors, Estrogen / administration & dosage*
  • Treatment Outcome

Substances

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