Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou, China.
Blood. 2011 Feb 10;117(6):1986-97. doi: 10.1182/blood-2010-05-284810. Epub 2010 Dec 6.
D-cyclins are universally dysregulated in multiple myeloma and frequently overexpressed in leukemia. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high-throughput screen for inhibitors of cyclin D2 transactivation and identified 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161), which inhibited the expression of cyclins D1, D2, and D3 and arrested cells at the G(0)/G(1) phase. After D-cyclin suppression, S14161 induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of leukemia, S14161 inhibited tumor growth without evidence of weight loss or gross organ toxicity. Mechanistically, S14161 inhibited the activity of phosphoinositide 3-kinase in intact cells and the activity of the phosphoinositide 3-kinases α, β, δ, and γ in a cell-free enzymatic assay. In contrast, it did not inhibit the enzymatic activities of other related kinases, including the mammalian target of rapamycin, the DNA-dependent protein kinase catalytic subunit, and phosphoinositide-dependent kinase-1. Thus, we identified a novel chemical compound that inhibits D-cyclin transactivation via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Given its potent antileukemia and antimyeloma activity and minimal toxicity, S14161 could be developed as a novel agent for blood cancer therapy.
D 型细胞周期蛋白在多发性骨髓瘤中普遍失调，在白血病中常过度表达。为了更好地了解失调的 D 型细胞周期蛋白在血液恶性肿瘤中的作用和影响，我们进行了 D 型细胞周期蛋白 2 反式激活抑制剂的高通量筛选，并鉴定出 8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯（S14161），它能抑制细胞周期蛋白 D1、D2 和 D3 的表达，并使细胞停滞在 G0/G1 期。在骨髓瘤和白血病细胞系以及原发性患者样本中，D-细胞周期蛋白抑制后，S14161 诱导细胞凋亡，而对正常造血细胞的作用则相对较小。在白血病小鼠模型中，S14161 抑制肿瘤生长，而没有体重减轻或明显器官毒性的证据。在机制上，S14161 在完整细胞中抑制磷酸肌醇 3-激酶的活性，在无细胞酶测定中抑制磷酸肌醇 3-激酶 α、β、δ 和 γ 的活性。相比之下，它不抑制其他相关激酶的酶活性，包括雷帕霉素的哺乳动物靶蛋白、DNA 依赖性蛋白激酶催化亚基和磷酸肌醇依赖性激酶-1。因此，我们鉴定了一种新型化学化合物，它通过磷酸肌醇 3-激酶/蛋白激酶 B 信号通路抑制 D 型细胞周期蛋白的反式激活。鉴于其强大的抗白血病和抗骨髓瘤活性和最小的毒性，S14161 可被开发为血液癌症治疗的新型药物。
