Anticancer activity of novel unnatural synthetic isoprenoids.
Anticancer activity of novel unnatural synthetic isoprenoids.
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发表时间：
2010-07
影响因子：
2
通讯作者：
V. Adams;D. DeRemer;Bojana Stevich;C. Mattingly;Becky Gallt;T. Subramanian;J. Troutman;H. Spielmann
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文献类型：
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作者：
V. Adams;D. DeRemer;Bojana Stevich;C. Mattingly;Becky Gallt;T. Subramanian;J. Troutman;H. Spielmann
背景KRAS癌基因在实体恶性肿瘤中的患病率很高。靶向KRAS和MAPK通路的不适当激活与新的药物是感兴趣的。这项研究开发并筛选了一个化合物库，旨在通过改变异戊二烯基功能来抑制KRAS信号传导。材料和方法筛选新的法呢基类似物的文库，以确定它们在人肺癌和乳腺癌细胞系中的抗癌活性。评价设计和实际药理学是否一致。结果67个新化合物进行了测试，其中70%的筛选阳性至少在一个细胞系的活性。两种活性化合物抑制MAP激酶的磷酸化与KRAS抑制一致。结论67种新药中有47种活性阳性，但没有一种是高效的。然而，用与蛋白质的法呢基和香叶基香叶基修饰竞争的化合物靶向RAS仍然是可行的，并且已经在进行进一步的工作以创建第二代分子。
BACKGROUND The KRAS oncogene has a high prevalence in solid malignancies. Targeting KRAS and inappropriate activation of the MAPK pathway with novel drugs is of interest. This study developed and screened a library of compounds designed to inhibit KRAS signaling by altering prenyl function. MATERIALS AND METHODS To screen a library of novel farnesyl analogs for their anticancer activity in human lung cancer and breast cancer cell lines. To evaluate if the designed and actual pharmacology are congruent. RESULTS Sixty-seven novel compounds were tested and 70% of them screened positive for activity in at least one cell line. Two active compounds inhibited phosphorylation of MAP kinase consistent with KRAS inhibition. CONCLUSION Although 47 of the 67 novel agents screened positive for activity, none of them were highly potent. However, targeting RAS with compounds that compete with farnesyl and geranylgeranyl modification of the protein remains viable and further work is already underway to create second generation molecules.