CB-03–10 (cortexolone 17α-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03–05 (cortexolone 17α-valerate) included in vitro binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional activities, and screening for antitumor activity across a selected panel of human prostate and in triple-negative breast cancer cell lines. CB-03-10 cytotoxic activity in these cancer cell lines was in the low micromolar range and was primarily associated with induction of the apoptotic cascade via activation of caspases. The compound's potential for antitumor activity was verified in a murine xenograft model utilizing the AR-positive LNCaP prostate cancer cell line as well as in an orthotopic model utilizing AR-negative/GR-positive MDA-MB-231 breast cancer cell line. Orally administered CB-03-10 inhibited prostate tumor growth and orthotopically implanted breast tumor growth in these mice and maintained body weight, as compared with vehicle-treated mice. On the basis of AR/GR binding affinities, antagonism of androgen and glucocorticoid-dependent transcriptional activities, and AR/GR mRNA and protein expression, the mechanism of tumor growth suppression is related to AR and GR antagonist activities. Importantly, these compounds lack biologically relevant AR/GR agonist activities. Overall, these preclinical findings support the selection of CB-03-10 for further development as an anticancer agent in cases where resistance to AR-targeted therapy or chemotherapy, via upregulation of GR activity, continues to limit the efficacy and duration of clinical benefit with these interventions.

中文翻译：

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双雄激素受体和糖皮质激素受体拮抗剂 CB-03-10 作为潜在治疗已获得 GR 介导的对 AR 阻断的抗性的肿瘤

CB-03-10 (cortexolone 17α-valerate-21-propionate) 是一种合成甾体化合物，来源于皮质醇生物合成的中间体 cortexolone (11-deoxycortisone)。CB-03-10 及其主要相关化合物 CB-03-05（cortexolone 17α-valerate）的活性表征包括体外结合雄激素和糖皮质激素受体（AR 和 GR），拮抗 AR 和 GR 转录活性，在选定的一组人前列腺和三阴性乳腺癌细胞系中筛选抗肿瘤活性。这些癌细胞系中的 CB-03-10 细胞毒活性处于低微摩尔范围内，主要与通过激活半胱天冬酶诱导凋亡级联相关。化合物' 在使用 AR 阳性 LNCaP 前列腺癌细胞系的鼠异种移植模型以及使用 AR 阴性/GR 阳性 MDA-MB-231 乳腺癌细胞系的原位模型中验证了其抗肿瘤活性的潜力。与载体处理的小鼠相比，口服 CB-03-10 抑制了这些小鼠的前列腺肿瘤生长和原位植入的乳腺肿瘤生长，并保持了体重。基于AR/GR结合亲和力、拮抗雄激素和糖皮质激素依赖的转录活性以及AR/GR mRNA和蛋白表达，肿瘤生长抑制机制与AR和GR拮抗剂活性有关。重要的是，这些化合物缺乏生物学相关的 AR/GR 激动剂活性。全面的，