Liang Jun, Blake Robert, Chang Jae, Friedman Lori S, Goodacre Simon, Hartman Steven, Ingalla Ellen Rei, Kiefer James R, Kleinheinz Tracy, Labadie Sharada, Li Jun, Lai Kwong Wah, Liao Jiangpeng, Mody Vidhi, McLean Neville, Metcalfe Ciara, Nannini Michelle, Otwine Daniel, Ran Yingqing, Ray Nick, Roussel Fabien, Sambrone Amy, Sampath Deepak, Vinogradova Maia, Wai John, Wang Tao, Yeap Kuen, Young Amy, Zbieg Jason, Zhang Birong, Zheng Xiaoping, Zhong Yu, Wang Xiaojing
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Charles River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
ACS Med Chem Lett. 2020 May 26;11(6):1342-1347. doi: 10.1021/acsmedchemlett.0c00224. eCollection 2020 Jun 11.
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of that showed ionic interaction of azetidine with Asp351 residue. Importantly, showed favorable metabolic stability and good oral exposure. exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
雌激素受体α（ERα）是雌激素受体阳性（ER+）乳腺癌经过充分验证的药物靶点。氟维司群已获美国食品药品监督管理局（FDA）批准用于治疗ER+乳腺癌，其作用机制有两种——作为完全拮抗剂和选择性雌激素受体降解剂（SERD），但口服生物利用度较低。因此，我们设想了一种与氟维司群具有相同双重机制但口服暴露量显著的“同类最佳”分子。通过先导化合物优化，我们发现了一种工具分子（GNE-149），它在MCF7和T47D细胞中具有改善的降解和抗增殖活性。为了阐明该支架与ERα的结合模式和关键相互作用，我们获得了其共晶体结构，该结构显示氮杂环丁烷与Asp351残基存在离子相互作用。重要的是，其表现出良好的代谢稳定性和口服暴露量。在子宫中表现出拮抗作用，并在异种移植模型中显示出强大的剂量依赖性疗效。
