Novel Substrate Competitive Bcr-Abl Inhibitor Active Against Gleevec-Resistant CM

新型底物竞争性 Bcr-Abl 抑制剂对格列卫耐药 CM 具有活性

• 批准号: 7046281
• 负责人: E Premkumar Reddy
• 金额: $ 37.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-02 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046281
• 关键词: antineoplastics; apoptosis; athymic mouse; biological signal transduction; cell cycle; chronic myelogenous leukemia; combination chemotherapy; drug interactions; drug resistance; drug screening /evaluation; gene mutation; kinase inhibitor; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; nonhuman therapy evaluation; oncogenes; pharmacokinetics; protein tyrosine kinase; xenotransplantation

DESCRIPTION (provided by applicant): Imatinib, which is an inhibitor of BCR-ABL tyrosine kinase and used for the treatment of human CML, has been a spectacular success. However, a significant proportion of patients chronically treated with imatinib develop resistance due to acquisition of mutations in the kinase domain of BCR-ABL. We have recently developed a compound (ON012380) that binds to BCR-ABL at a site different from imatinib and induces apoptosis of Ph+ CML cells at a concentration of 5-10 nM (which is 10-50 fold more potent than imatinib). More interestingly, this compound was found to be very effective in inducing the death of all of the imatinib-resistant mutants of CML identified so far. In this application, we propose to carry out a detailed biochemical characterization of the mechanism of action of this compound and the nature of signaling pathways that are affected by this compound. The aims are: 1. To determine the kinetics of inhibition of BCR-ABL by ON012380 and carry out in vitro screen of mutagenized BCR-ABL clones to gain an understanding of the amino acid substitutions that are likely to impair the binding of ON012380. 2. To determine the effects of ON012380 on (a) wild-type and imatinib-resistant mutants of BCR-ABL on the kinase activity; (b) downstream signaling such as MAPK, AKT and STAT5 activation (c) cell cycle progression; and (d) the nature of apoptotic pathways activated in tumor cells that express wild-type or mutant BCR-ABL protein. 3. Determine whether ON012380 induces cell death of Lyn overexpressing, imatinib resistant cells and if so, determine the mechanism of action. 4. Conduct pharmacokinetic studies by the route and schedule used for efficacy studies, and 5. Conduct efficacy trials in established xenograft models of CML.

描述（由申请人提供）：伊马替尼是BCR-ABL酪氨酸激酶的抑制剂，用于治疗人CML，已经取得了巨大的成功。然而，由于获得BCR-ABL的激酶结构域的突变，因此长期用伊马替尼长期治疗的患者会产生抗药性。我们最近开发了一种化合物（ON012380），该化合物与与伊马替尼不同的位点上的BCR-ABL结合，并以5-10 nm的浓度诱导pH+ CML细胞的凋亡（比伊马替尼的效力更高10-50倍）。更有趣的是，发现该化合物在诱导迄今为止鉴定出的所有伊马替尼的CML突变体的死亡方面非常有效。在此应用中，我们建议对该化合物的作用机理以及受该化合物影响的信号传导途径的性质进行详细的生化表征。目的是：1。确定ON012380对BCR-ABL抑制的动力学，并在体外对诱变BCR-ABL克隆进行体外筛选，以了解可能会损害ON012380结合的氨基酸取代。 2。确定ON012380对BCR-ABL（a）野生型和伊马替尼抗性突变体对激酶活性的影响； （b）下游信号传导，例如MAPK，AKT和STAT5激活（C）细胞周期进程； （d）在表达野生型或突变体BCR-ABL蛋白的肿瘤细胞中激活的凋亡途径的性质。 3。确定ON012380是否诱导Lyn过表达，伊马替尼耐药细胞的细胞死亡，如果是这样，请确定作用机理。 4。通过用于疗效研究的路线和时间表进行药代动力学研究，5。在已建立的CML的异种移植模型中进行功效试验。