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

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.

• Authors: James D Joseph, Beatrice Darimont, Wei Zhou, Alfonso Arrazate, Amy Young, Ellen Ingalla, Kimberly Walter, Robert A Blake, Jim Nonomiya, Zhengyu Guan, Lorna Kategaya, Steven P Govek, Andiliy G Lai, Mehmet Kahraman, Dan Brigham, John Sensintaffar, Nhin Lu, Gang Shao, Jing Qian, Kate Grillot, Michael Moon, Rene Prudente, Eric Bischoff, Kyoung-Jin Lee, Celine Bonnefous, Karensa L Douglas, Jackaline D Julien, Johnny Y Nagasawa, Anna Aparicio, Josh Kaufman, Benjamin Haley, Jennifer M Giltnane, Ingrid E Wertz, Mark R Lackner, Michelle A Nannini, Deepak Sampath, Luis Schwarz, Henry Charles Manning, Mohammed Noor Tantawy, Carlos L Arteaga, Richard A Heyman, Peter J Rix, Lori Friedman, Nicholas D Smith, Ciara Metcalfe, Jeffrey H Hager
• Journal: eLife (Elife) Vol. 5 (07 13 2016) ISSN: 2050-084X [Electronic] England
• PMID: 27410477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

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
• Indazoles
• Receptors, Estrogen

Topics

• 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