Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule.
Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule.
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DOI：
10.1021/jm900424a
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发表时间：
2009-06-25
影响因子：
7.3
通讯作者：
Neidle S
中科院分区：
文献类型：
--
作者：
Gunaratnam M;Swank S;Haider SM;Galesa K;Reszka AP;Beltran M;Cuenca F;Fletcher JA;Neidle S
大多数人胃肠道间质瘤（GIST）是由原癌基因KIT（一种酪氨酸激酶受体）中的激活突变驱动的。伊马替尼的临床治疗靶向KIT的激酶结构域，但由于激酶活性位点发生耐药突变，肿瘤再生长发生。描述了GIST治疗的另一种小分子方法，其中KIT基因被直接靶向，因此可以规避激酶抗性。萘二酰亚胺衍生物已被用于证明双重四链体靶向的概念。该化合物在体外强烈稳定端粒四链体DNA和KIT启动子中的四链体位点。本文表明，该化合物在一定浓度（约1μM）下是患者源性GIST细胞系生长停滞的强效诱导剂，该浓度还可有效抑制端粒酶活性，并几乎完全抑制KIT mRNA和KIT蛋白表达。端粒四链体的分子建模研究已被用来合理化方面的实验四链体熔化数据。
The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data.
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影响因子：
14.9
作者：
Gomez, D;Lemarteleur, T;Riou, JF
通讯作者：
Riou, JF
影响因子：
6.1
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
TrisubStttestated的异丙恶唑作为新的G四链体结合配体：C-KIT癌基因表达的小分子调节。
影响因子：
15
作者：
Bejugam, Mallesham;Sewitz, Sven;Shirude, Pravin S.;Rodriguez, Raphael;Shahid, Ramla;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
2.7
作者：
Cuenca, Francisco;Greciano, Olga;Neidle, Stephen
通讯作者：
Neidle, Stephen
影响因子：
45.3
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
通讯作者：
Fletcher, JA