The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

中文翻译：

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Palazestrant (OP-1250) 是一种完全雌激素受体拮抗剂，可单独或联合治疗野生型和突变型 ER 阳性乳腺癌模型

雌激素受体 (ER) 是乳腺癌治疗的既定靶标，大多数患者表现为 ER 阳性 (ER+)。内分泌治疗是乳腺癌治疗的支柱，但芳香酶抑制剂产生的耐药突变、氟维司群的药代动力学特性较差、他莫昔芬的激动剂活性以及 elacestrant 的获益有限，导致对 ESR1 存在或不存在耐药突变的患者的需求未得到满足。编码 ER 蛋白的基因。在这里，我们描述了 palazestrant (OP-1250)，一种新型、口服生物可利用的完全 ER 拮抗剂和选择性 ER 降解剂。OP-1250 与氟维司群一样，对 ER 没有激动剂活性，并完全阻断雌激素诱导的转录活性。此外，OP-1250 在 ER+ 乳腺癌模型中表现出良好的生化结合亲和力、ER 降解和抗增殖活性，与其他感兴趣的药物相当或优于它们。OP-1250 相对于氟维司群具有优异的药代动力学特性，包括口服生物利用度和脑渗透率，以及在野生型和 ESR1 突变乳腺癌异种移植研究中的优异表现。在 ER+ 乳腺癌模型的异种移植研究中，OP-1250 与细胞周期蛋白依赖性激酶 4 和 6 抑制剂良好结合，可有效缩小颅内植入的肿瘤，从而延长动物生存期。OP-1250 的临床前疗效已在野生型模型中超过氟维司群、在 ESR1 突变模型中超过 elacestrant 以及在颅内异种移植物中超过他莫昔芬，因此有可能使 ER+ 乳腺癌患者受益。