A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway
A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway
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DOI：
10.1182/blood-2010-05-284810
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发表时间：
2011-02-10
期刊：
影响因子：
20.3
通讯作者：
Schimmer, Aaron D.
中科院分区：
文献类型：
--
作者：
Mao, Xinliang;Cao, Biyin;Schimmer, Aaron D.
D-细胞周期蛋白在多发性骨髓瘤中普遍表达异常，在白血病中经常过表达。为了更好地了解调控失调的D-细胞周期蛋白在血液系统恶性肿瘤中的作用和影响，我们对细胞周期蛋白D2反式激活的抑制物进行了高通量筛选，并确定了8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene(S14161)，它抑制细胞周期蛋白D1、D2和D3的表达，并将细胞停滞在G(0)/G(1)期。在抑制D-细胞周期蛋白后，S14161优先诱导骨髓瘤和白血病细胞系和原发患者样本的凋亡。在白血病小鼠模型中，S14161在没有体重减轻或大体器官毒性的情况下抑制了肿瘤的生长。机制上，S14161抑制完整细胞中肌醇磷脂3-激酶的活性，并在无细胞酶分析中抑制肌醇磷脂3-激酶α、β、β和γ的活性。相反，它不抑制其他相关酶的活性，包括哺乳动物靶标雷帕霉素、DNA依赖的蛋白激酶催化亚基和磷脂酰肌醇依赖的激酶-1。因此，我们确定了一种新的化合物，它通过磷脂酰肌醇3-激酶/蛋白激酶B信号通路抑制D-细胞周期蛋白的反式激活。S14161具有较强的抗白血病和抗骨髓瘤活性，毒性小，有望成为治疗血癌的新型药物。(血。2011；117(6)：1986-1997)
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 alpha, beta, delta, and gamma 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. (Blood. 2011; 117(6): 1986-1997)