Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada.
Department of Surgery, Division of Urology, McGill University and the Cancer Research Program of the Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Bioorg Med Chem Lett. 2022 Jan 1;55:128441. doi: 10.1016/j.bmcl.2021.128441. Epub 2021 Nov 9.
The combination of androgen receptor antagonists with histone deacetylase inhibitors (HDACi) has been shown to be more effective than antiandrogens alone in halting growth of prostate cancer cell lines. Here we have designed, synthesized and assessed a series of antiandrogen/HDACi hybrids by combining structural features of enzalutamide with either SAHA or entinostat. The hybrids are demonstrated to maintain bifunctionality using a fluorometric HDAC assay and a bioluminescence resonance energy transfer (BRET) antiandrogen assay. Antiproliferative assays showed that hybrids bearing o-aminoanilide-based HDACi motifs outperformed hydroxamic acid based HDACi's. The hybrids demonstrated selectivity for epithelial cell lines vs. stromal cell lines, suggesting a potentially useful therapeutic window.
雄激素受体拮抗剂与组蛋白去乙酰化酶抑制剂（HDACi）的联合应用已被证明比单独使用抗雄激素更能有效阻止前列腺癌细胞系的生长。在这里，我们通过将恩扎鲁胺的结构特征与 SAHA 或entinostat 相结合，设计、合成并评估了一系列的抗雄激素/HDACi 杂合体。通过荧光 HDAC 测定法和生物发光共振能量转移（BRET）抗雄激素测定法，证明这些杂合体保持了双功能特性。增殖抑制试验表明，带有邻氨基苯甲酰胺基 HDACi 基序的杂合体优于基于羟肟酸的 HDACi。这些杂合体对上皮细胞系与基质细胞系的选择性表明，它们具有潜在的有用的治疗窗口。
