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Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-05-22 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00054 Andiliy Lai 1 , Mehmet Kahraman 1 , Steven Govek 1 , Johnny Nagasawa 1 , Celine Bonnefous 1 , Jackie Julien 1 , Karensa Douglas 1 , John Sensintaffar 1 , Nhin Lu 1 , Kyoung-jin Lee 1 , Anna Aparicio 1 , Josh Kaufman 1 , Jing Qian 1 , Gang Shao 1 , Rene Prudente 1 , Michael J. Moon 1 , James D. Joseph 1 , Beatrice Darimont 1 , Daniel Brigham 1 , Kate Grillot 1 , Richard Heyman 1 , Peter J. Rix 1 , Jeffrey H. Hager 1 , Nicholas D. Smith 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-05-22 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00054 Andiliy Lai 1 , Mehmet Kahraman 1 , Steven Govek 1 , Johnny Nagasawa 1 , Celine Bonnefous 1 , Jackie Julien 1 , Karensa Douglas 1 , John Sensintaffar 1 , Nhin Lu 1 , Kyoung-jin Lee 1 , Anna Aparicio 1 , Josh Kaufman 1 , Jing Qian 1 , Gang Shao 1 , Rene Prudente 1 , Michael J. Moon 1 , James D. Joseph 1 , Beatrice Darimont 1 , Daniel Brigham 1 , Kate Grillot 1 , Richard Heyman 1 , Peter J. Rix 1 , Jeffrey H. Hager 1 , Nicholas D. Smith 1
Affiliation
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Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
中文翻译：
GDC-0810（ARN-810）的鉴定，这是一种口服可生物利用的选择性雌激素受体降解剂（SERD），可在抗他莫昔芬的乳腺癌异种移植物中显示出强劲的活性。
大约80％的乳腺癌是雌激素受体α（ER-α）阳性，尽管女性通常最初对他莫昔芬和芳香酶抑制剂等抗激素疗法反应良好，但通常会出现耐药性。尽管在这种状态下可能有多种耐药机制起作用，但有证据表明，在许多情况下，内质网仍起着中心作用，包括内质网中的突变导致组成性活性受体。Fulvestrant是一种基于类固醇的选择性雌激素受体降解剂（SERD），可拮抗和降解ER-α，并在抗激素药物治疗的患者中活跃。然而，氟维司群具有较差的药物特性，必须通过肌内注射来给药，这限制了可以给药的药物总量，因此可能导致不完全的受体阻滞。我们描述了一系列小分子，口服生物可利用的SERDs的鉴定和表征，这些SERDs是ER-α的强效拮抗剂和降解剂，并且预期地优化了ER-α的降解性能。铅化合物11l（GDC-0810或ARN-810）在他莫昔芬敏感和他莫昔芬耐药的乳腺癌模型中显示出强大的活性，目前正在对患有局部晚期或转移性雌激素受体阳性乳腺癌的妇女进行临床试验。
更新日期：2015-05-22
中文翻译：
GDC-0810（ARN-810）的鉴定，这是一种口服可生物利用的选择性雌激素受体降解剂（SERD），可在抗他莫昔芬的乳腺癌异种移植物中显示出强劲的活性。
大约80％的乳腺癌是雌激素受体α（ER-α）阳性，尽管女性通常最初对他莫昔芬和芳香酶抑制剂等抗激素疗法反应良好，但通常会出现耐药性。尽管在这种状态下可能有多种耐药机制起作用，但有证据表明，在许多情况下，内质网仍起着中心作用，包括内质网中的突变导致组成性活性受体。Fulvestrant是一种基于类固醇的选择性雌激素受体降解剂（SERD），可拮抗和降解ER-α，并在抗激素药物治疗的患者中活跃。然而，氟维司群具有较差的药物特性，必须通过肌内注射来给药，这限制了可以给药的药物总量，因此可能导致不完全的受体阻滞。我们描述了一系列小分子，口服生物可利用的SERDs的鉴定和表征，这些SERDs是ER-α的强效拮抗剂和降解剂，并且预期地优化了ER-α的降解性能。铅化合物11l（GDC-0810或ARN-810）在他莫昔芬敏感和他莫昔芬耐药的乳腺癌模型中显示出强大的活性，目前正在对患有局部晚期或转移性雌激素受体阳性乳腺癌的妇女进行临床试验。
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