已经批准了靶向雌激素受体降解作为有效治疗ER+乳腺癌的方法。由于富来雌酮（SERD）的生物利用度较低，许多努力都致力于开发口服SERDs。随着Elacestrant的批准，口服SERDs显示出比富来雌酮更佳的疗效。然而，由于已知SERDs穿透血脑屏障的能力较差，患有脑转移的乳腺癌患者无法从临床上使用SERDs获益。采用了ERα蛋白降解、靶基因下调的评价去评估ER的抑制效果。抗增殖活性在一系列ER+乳腺癌细胞系中进一步确定。亚皮下和颅内ER+肿瘤模型被用于评估抗肿瘤效果的疗效。多种动物种类通过大脑渗透性进行了确定。SCR-6852是一种新型SERD，目前处于早期临床评估阶段。体外研究表明，它能很好地诱导野生型和突变型ERα的降解。它在一系列含有ESR1突变（Y537和D538）的ER+乳腺癌细胞系中有效地抑制了细胞增殖。此外，SCR-6852在体内外均表现出对ERɑ信号轴的纯拮抗活性。SCR-6852以10mg/kg的口服剂量使肿瘤持续缩小，该剂量优于250mg/kg的富来雌酮，尤其在颅内肿瘤模型中，SCR-6852能有效抑制肿瘤生长，显著延长小鼠的存活期，与大脑中的高暴露程度相一致。除小鼠外，SCR-6852在大鼠和狗中也具有高的大脑渗透性。SCR-6852是一种新型的SERD，在体外和体内诱导ERα蛋白降解、对ERɑ信号通路展示纯拮抗活性方面具有很高的效力。由于其高的大脑渗透性，SCR-6852可能被用于治疗患有脑转移的乳腺癌患者。© 2023. BioMed Central Ltd., part of Springer Nature.

Targeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develop oral SERDs. With the approval of Elacestrant, oral SERDs demonstrated superior efficacy than fulvestrant. However, due to the poor ability of known SERDs to penetrate the blood-brain barrier (BBB), breast cancer patients with brain metastasis cannot benefit from clinical SERDs.The ER inhibitory effects were evaluated on ERα protein degradation, and target genes downregulation. And anti-proliferation activities were further determined in a panel of ER + breast cancer cell lines. The subcutaneous and intracranial ER + tumor models were used to evaluate the efficacy of anti-tumor effects. Brain penetrability was determined in multiple animal species.SCR-6852 is a novel SERD and currently is under early clinical evaluation. In vitro studies demonstrated that it strongly induced both wildtype and mutant ERα degradation. It potently inhibited cell proliferation in a panel of ER + breast cancer cell lines, including the cell lines containing ESR1 mutations (Y537 and D538). Furthermore, SCR-6852 exhibited pure antagonistic activities on the ERɑ signal axis identified both in vitro and in vivo. Oral administration of SCR-6852 at 10 mg/kg resulted in tumor shrinkage which was superior to Fulvestrant at 250 mg/kg, notably, in the intracranial tumor model, SCR-6852 effectively inhibited tumor growth and significantly prolonged mice survival, which correlated well with the high exposure in brains. In addition to mice, SCR-6852 also exhibited high brain penetrability in rats and dogs.SCR-6852 is a novel SERD with high potency in inducing ERα protein degradation and pure antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.© 2023. BioMed Central Ltd., part of Springer Nature.