Zhang Dan, Lu Zhengyu, He Yongqi, Leng Xin-Yu, Meng Xin, Lei Xiang, Kong Deyu, Sun Lulu, Hu Wenhao, Yang Yushe
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
J Med Chem. 2024 Dec 12;67(23):21545-21567. doi: 10.1021/acs.jmedchem.4c02453. Epub 2024 Nov 28.
Selective estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ERα and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds . This bifunctional compound displayed broad activity across a vast array of cell backgrounds and was capable of effectively degrading and antagonizing wild-type ERα and clinically relevant ERα mutants. exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.
选择性雌激素受体降解剂（SERDs）通过拮抗和降解雌激素受体α（ERα）来耗尽ER信号通路，是解决内分泌耐药性的一种有前景的策略。在此，我们通过对选择性雌激素受体调节剂拉索昔芬进行药理学改造，报告了一类新型的SERDs。结构-活性关系研究以及解决人类醚-去极化相关基因问题的努力，促成了化合物的鉴定。这种双功能化合物在大量细胞背景中均表现出广泛的活性，并且能够有效降解和拮抗野生型ERα以及临床相关的ERα突变体。其具有良好的药代动力学性质和良好的脑渗透性，脑/血浆比为3.05，并且在他莫昔芬耐药的MCF-7 Tam1异种移植模型中显著抑制肿瘤生长。总体而言，该研究证明其为一种高效、口服且具有脑渗透性的ER降解剂和纯拮抗剂，在克服内分泌耐药性方面显示出良好的潜力。
