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

• DOI: 10.7554/elife.15828
• Publication Date: 2016-07-13T11:59:41Z
• 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 Man...; Mohammed Noor Tan...; Carlos L Arteaga; Richard A Heyman; Peter J Rix; Lori Friedman; Nicholas D Smith; Ciara Metcalfe; Jeffrey H Hager
• Keywords: Indazoles; QH301-705.5; Science; Antineoplastic Agents; Breast Neoplasms; Mice; breast cancer; Cell Line, Tumor; Animals; Humans; Prospective Studies; Biology (General); Cancer Biology; GDC-0810; Q; R; Rats; 3. Good health; Disease Models, Animal; Treatment Outcome; Receptors, Estrogen; Cinnamates; SERD; Medicine; Heterografts; estrogen receptor

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