Joseph James D, Darimont Beatrice, Zhou Wei, Arrazate Alfonso, Young Amy, Ingalla Ellen, Walter Kimberly, Blake Robert A, Nonomiya Jim, Guan Zhengyu, Kategaya Lorna, Govek Steven P, Lai Andiliy G, Kahraman Mehmet, Brigham Dan, Sensintaffar John, Lu Nhin, Shao Gang, Qian Jing, Grillot Kate, Moon Michael, Prudente Rene, Bischoff Eric, Lee Kyoung-Jin, Bonnefous Celine, Douglas Karensa L, Julien Jackaline D, Nagasawa Johnny Y, Aparicio Anna, Kaufman Josh, Haley Benjamin, Giltnane Jennifer M, Wertz Ingrid E, Lackner Mark R, Nannini Michelle A, Sampath Deepak, Schwarz Luis, Manning Henry Charles, Tantawy Mohammed Noor, Arteaga Carlos L, Heyman Richard A, Rix Peter J, Friedman Lori, Smith Nicholas D, Metcalfe Ciara, Hager Jeffrey H
Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
Department of Translational Oncology, Genentech, South San Francisco, United States.
Elife. 2016 Jul 13;5:e15828. doi: 10.7554/eLife.15828.
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.
雌激素受体（ER）靶向疗法为雌激素受体阳性（ER+）乳腺癌患者提供了有价值的治疗选择，然而，目前的复发率和死亡率凸显了改进治疗策略的必要性。最近在复发肿瘤中发现普遍存在的ESR1突变，强调了晚期肿瘤对ERα信号传导的持续依赖，并为继续靶向ERα提供了有力的理论依据。在此，我们描述了GDC-0810，一种新型的、非甾体类、口服生物可利用的选择性雌激素受体下调剂（SERD），它是通过前瞻性优化ERα降解、拮抗作用和药代动力学特性而确定的。相对于目前批准的治疗药物所诱导的构象，GDC-0810诱导出一种独特的ERα构象，提示其作用机制独特。GDC-0810对多种人乳腺癌细胞系和患者来源的异种移植瘤具有强大的体外和体内活性，包括他莫昔芬耐药模型以及那些携带ERα突变的模型。GDC-0810目前正在ER+乳腺癌女性患者中进行II期临床研究评估。
