Govek Steven P, Nagasawa Johnny Y, Douglas Karensa L, Lai Andiliy G, Kahraman Mehmet, Bonnefous Celine, Aparicio Anna M, Darimont Beatrice D, Grillot Katherine L, Joseph James D, Kaufman Joshua A, Lee Kyoung-Jin, Lu Nhin, Moon Michael J, Prudente Rene Y, Sensintaffar John, Rix Peter J, Hager Jeffrey H, Smith Nicholas D
Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
Seragon Pharmaceuticals, Inc., 12780 El Camino Real, Suite 302, San Diego, CA 92130, United States.
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5163-7. doi: 10.1016/j.bmcl.2015.09.074. Epub 2015 Oct 3.
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
选择性雌激素受体降解剂(SERDs)已显示出治疗雌激素受体阳性(ER+)乳腺癌的潜力。本文公开了我们对吲唑类SERDs的持续优化。通过体外雌激素受体降解和拮抗作用的探索,随后进行体内拮抗和口服暴露试验,最终发现了吲唑47和56,它们可在他莫昔芬耐药的乳腺癌异种移植模型中诱导肿瘤消退。