Targeting of NQ02 in CML

CML 中 NQ02 的靶向

• 批准号: 7742380
• 负责人: DAVID ROSS
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742380
• 关键词: Apoptosis; Archives; Binding; Blast Phase; Cell Line; Cells; Chronic; Chronic Disease; Chronic Myeloid Leukemia; Complement; Development; Disease Progression; Enzymes; Genetic; Growth; Human; Imatinib; Immunoblotting; In Vitro; Indolequinones; Laboratories; Lead; Measurement; Measures; Molecular Conformation; Myeloid Cells; NQO1 gene; NRH - quinone oxidoreductase2; Necrosis; Outcome; Patients; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Quinone Reductases; Recombinants; Research Design; Resistance; Role; Sampling; Series; Specificity; Structure; Testing; Therapeutic; Work; base; bcr-abl Fusion Proteins; cell growth; enzyme activity; inhibitor/antagonist; novel; novel therapeutic intervention; protein protein interaction; public health relevance; small hairpin RNA; small molecule; suicide inhibitor

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）：伊马替尼被开发用于专门针对慢性粒细胞白血病（CML）中癌蛋白 BCR-ABL 失调的酪氨酸激酶活性，并且对其主要激酶靶点具有高度特异性。 2007 年的一项令人惊讶且意想不到的发现，在两项独立研究中，NQO2 被确定为伊马替尼的第一个非激酶靶标。研究发现伊马替尼能够与 NQO2 有效且特异性地结合，从而抑制该酶的催化活性。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。在本提案中，我们将定义专门针对 CML 中的 NQO2 的结果。 NQO2 水平尚未在人类 CML 中进行检查，在目标 1 中，我们将表征一组未经伊马替尼和伊马替尼耐药的存档 CML 患者样本中的 NQO2 水平。在目标 2 中，我们将检查使用我们实验室开发的新型基于机制的（自杀）抑制剂特异性靶向 NQO2 是否会在人类 CML 细胞系中产生抗增殖活性。我们还将通过使用抗 NQO2 shRNA 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 稳定性会受到与其他蛋白质相互作用的影响。因此，在目标 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，这种相互作用是否被伊马替尼抑制，它是否导致 BCR-ABL 稳定性增加以及它是否取决于 NQO2 的催化活性。拟议的研究将描述 NQO2 在伊马替尼治疗活性中的潜在作用，并确定专门针对 NQO2 作为 CML 治疗方法的结果。公共健康相关性：已发现伊马替尼能与 NQO2 有效且特异性地结合，从而抑制该酶的催化活性。这项工作的意义在于，抑制 NQO2 可能有助于伊马替尼对慢性粒细胞白血病 (CML) 的治疗活性。拟议的研究将明确针对 CML 中专门针对 NQO2 的结果。 NQO2新型小分子自杀抑制剂的开发可能为CML提供新的治疗方法。