Mottamal Madhusoodanan, Kang Borui, Peng Xianyou, Wang Guangdi
Department of Chemistry, RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana 70125, United States.
ACS Omega. 2021 Mar 30;6(14):9334-9343. doi: 10.1021/acsomega.0c06362. eCollection 2021 Apr 13.
Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant. Oral SERDs that have been developed and tested in patients ranged from nonsteroidal ER binders containing an acrylic acid or amino side chain to bifunctional proteolysis-targeting chimera (PROTAC) pure ER degraders. Structural evolution in the development of oral SERD molecules has been closely associated with quantifiable ER-degrading potency, as seen in the structural comparison analysis of acrylic acid and basic amino side-chain-bearing SERDs. Failure to improve on fulvestrant in the clinical trials by numerous acidic SERDs and early basic SERDs is blamed on tolerability and/or insufficient efficacy, which will likely be overcome by the new-generation basic SERD molecules and PROTAC ER degraders with improved oral bioavailability, low toxicity, and superior efficacy of receptor degradation.
纯抗雌激素药物，即选择性雌激素受体降解剂（SERD），已被证明可有效治疗在他莫昔芬和/或芳香酶抑制剂治疗下病情进展的乳腺癌。然而，唯一获得美国食品药品监督管理局（FDA）批准的纯抗雌激素药物氟维司群，因其低生物利用度而疗效有限。寻找口服生物利用度高的SERD的研究几乎与仅注射用氟维司群的临床应用历史一样长。已在患者中研发和测试的口服SERD种类繁多，从含有丙烯酸或氨基侧链的非甾体雌激素受体（ER）结合剂到双功能蛋白酶靶向嵌合体（PROTAC）纯ER降解剂。口服SERD分子开发过程中的结构演变与可量化的ER降解效力密切相关，这在含丙烯酸和碱性氨基侧链的SERD的结构比较分析中可见一斑。许多酸性SERD和早期碱性SERD在临床试验中未能比氟维司群有更好的表现，原因在于耐受性和/或疗效不足，而新一代具有更高口服生物利用度、低毒性和更高效受体降解能力的碱性SERD分子和PROTAC ER降解剂可能会克服这些问题。
