Naasani I, Seimiya H, Yamori T, Tsuruo T
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Cancer Res. 1999 Aug 15;59(16):4004-11.
To facilitate the search for candidate telomerase inhibitors, we exploited the database of the disease-oriented screening program (DOS) available in our facility by using COMPARE analysis. In primary and arbitrary screening, we were able to identify the alkaloid berberine as a moderate inhibitor with 50% inhibition at approximately 35 microM. Using this alkaloid as a seed compound in COMPARE resulted in the identification of other berberine-like compounds and mitochondria-accumulating agents as highly related to berberine. Among these compounds, MKT077, a rhodacyanine derivative currently under Phase I clinical trials, showed a potent inhibitory effect with 50% inhibition at approximately 5 microM. With MKT077 as an upgraded seed for a new round of COMPARE analysis, we identified rhodacyanine FJ5002, a close derivative of MKT077, as the most potent telomerase inhibitor with 50% inhibition at approximately 2 microM. Long-term cultivation of U937, a human leukemia cell line, with subacute concentrations of FJ5002 resulted in population-doubling dependent changes characterized by progressive telomere erosion (from approximately 10 to approximately 4.0 kb), increased chromosome abnormalities, and senescence/crisis-like features. These results indicated that FJ5002 is a genuine and effective antitelomerase agent.
为便于寻找候选端粒酶抑制剂，我们利用本机构提供的疾病导向筛选程序（DOS）数据库进行COMPARE分析。在初步筛选和任意筛选中，我们能够鉴定出生物碱小檗碱为中度抑制剂，在约35微摩尔浓度时具有50%的抑制率。在COMPARE分析中以这种生物碱作为种子化合物，结果鉴定出其他类小檗碱化合物和线粒体聚集剂与小檗碱高度相关。在这些化合物中，MKT077，一种目前处于I期临床试验阶段的罗丹花青衍生物，在约5微摩尔浓度时显示出强效抑制作用，抑制率达50%。以MKT077作为新一轮COMPARE分析的升级种子，我们鉴定出MKT077的紧密衍生物罗丹花青FJ5002为最有效的端粒酶抑制剂，在约2微摩尔浓度时抑制率达50%。用人白血病细胞系U937长期培养于亚急性浓度的FJ5002，导致群体倍增依赖性变化，其特征为端粒逐渐缩短（从约10 kb至约4.0 kb）、染色体异常增加以及出现衰老/危机样特征。这些结果表明FJ5002是一种真正有效的抗端粒酶药物。
