Targeting of NQ02 in CML

CML 中 NQ02 的靶向

基本信息

批准号：
7903397
负责人：
DAVID ROSS
金额：
$ 19.13万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-30 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Imatinib was developed to target specifically the deregulated tyrosine kinase activity of the oncoprotein BCR-ABL in chronic myeloid leukemia (CML) and it has high specificity against its major kinase target. In a surprising and unexpected finding in 2007, NQO2 was identified as the first non-kinase target of imatinib in two independent studies. Imatinib was found to bind potently and specifically to NQO2 resulting in inhibition of catalytic activity of the enzyme. One of the conclusions of these two studies was that inhibition of NQO2 may contribute to the therapeutic activity of imatinib in CML cells. In this proposal, we will define the outcome of specifically targeting NQO2 in CML. Levels of NQO2 have not been examined in human CML and in aim 1 we will characterize NQO2 levels in a panel of imatinib-naive and imatinib resistant archived CML patient samples. In aim 2, we will examine whether specific targeting of NQO2 using novel mechanism-based (suicide) inhibitors developed in our laboratory results in antiproliferative activity in human CML cell lines. We will also validate the role of NQO2 in the proliferative activity of CML cells by employing anti-NQO2 shRNA and characterize the effect of stable knockdown of NQO2 on CML growth. BCR-ABL stability is known to be influenced by interactions with other proteins. In aim 3, we will therefore examine whether there is a protein-protein interaction between NQO2 and BCR-ABL, whether this interaction is inhibited by imatinib, whether it leads to increased stability of BCR-ABL and whether it depends on the catalytic activity of NQO2. The proposed studies will characterize the potential role of NQO2 in the therapeutic activity of imatinib and define the outcome of specifically targeting NQO2 as a therapeutic approach in CML. PUBLIC HEALTH RELEVANCE: Imatinib has been found to bind potently and specifically to NQO2 resulting in inhibition of catalytic activity of the enzyme. The implication of this work is that inhibition of NQO2 may contribute to the therapeutic activity of imatinib in chronic myeloid leukemia (CML). The proposed studies will define the outcome of specifically targeting NQO2 in CML. The development of novel small molecule suicide inhibitors of NQO2 may provide a novel therapeutic approach in CML.

描述（由申请人提供）：伊马替尼的开发是为了针对慢性髓样白血病（CML）中癌蛋白BCR-ABL的失调酪氨酸激酶活性，并且对其主要的激酶靶标具有很高的特异性。在2007年的一个令人惊讶和意外的发现中，NQO2在两项独立研究中被确定为伊马替尼的第一个非激酶靶标。发现伊马替尼可有效地与NQO2结合，从而抑制酶的催化活性。这两项研究的结论之一是，抑制NQO2可能有助于伊马替尼在CML细胞中的治疗活性。在此提案中，我们将定义针对CML中NQO2的结果的结果。在人CML中尚未检查NQO2的水平，在AIM 1中，我们将在一组伊马替尼（Imatinib-Naige）和伊马替尼（Imatinib）耐药的CML患者样品中表征NQO2水平。在AIM 2中，我们将使用基于机制的（自杀）抑制剂在实验室中开发的新型NQO2的特定靶向靶向，从而在人CML细胞系中产生抗增生活性。我们还将通过采用抗NQO2 shRNA来验证NQO2在CML细胞增殖活性中的作用，并表征NQO2稳定敲低对CML生长的影响。已知BCR-ABL稳定性受到与其他蛋白质相互作用的影响。因此，在AIM 3中，我们将检查NQO2和BCR-ABL之间是否存在蛋白质 - 蛋白质相互作用，这是否会被伊马替尼抑制，是否导致BCR-ABL的稳定性增加以及它是否取决于NQO2的催化活性。拟议的研究将表征NQO2在伊马替尼治疗活性中的潜在作用，并将特异性靶向NQO2作为CML治疗方法的结果定义。公共卫生相关性：已发现伊马替尼与NQO2有效地结合，从而导致酶的催化活性。这项工作的含义是抑制NQO2可能有助于伊马替尼在慢性髓样白血病（CML）中的治疗活性。拟议的研究将定义针对CML中NQO2的特异性结果。 NQO2的新型小分子自杀抑制剂的发展可能会在CML中提供一种新型的治疗方法。