Structural Biology of AML (CBFA2) and AML1-ETO

AML (CBFA2) 和 AML1-ETO 的结构生物学

• 批准号: 8462452
• 负责人: JOHN Hackett BUSHWELLER
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-04 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462452
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Adverse effects; Affinity; Apoptosis; Autologous; Binding; Biological Assay; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Cell Line; Cells; Chimeric Proteins; Core-Binding Factor; Cytogenetics; Development; Disease remission; Drug Design; Drug Formulations; Drug Kinetics; Event; Fluorescence Resonance Energy Transfer; Genes; Goals; Growth; Hematopoiesis; Hematopoietic; Human; Imatinib; Inhibitory Concentration 50; Lead; Ligands; Link; Methods; Mus; Mutation; Nature; Patients; Pharmaceutical Chemistry; Population; Production; Proteins; RUNX1 gene; Relapse; Residual state; Route; Stem cells; Structure; Testing; Time; Toxic effect; Transcript; Transplantation; base; chemotherapy; efficacy testing; experience; high throughput screening; improved; inhibitor/antagonist; leukemia; mouse model; protein protein interaction; public health relevance; runx proteins; self-renewal; small molecule; stem; structural biology; t(8; 21)(q22; q22); therapeutic target

DESCRIPTION (provided by applicant): The gene encoding Runx1 (AML1) is disrupted by the t(8;21) that is associated with ~12% of acute myeloid leukemia in humans. The t(8;21) results in production of a fusion protein containing the N-terminus of Runx1, including the Runt domain, fused to almost all of ETO. The AML1-ETO fusion protein acts as a dominant repressor of core binding factor function, dysregulating the expression of multiple genes required for normal hematopoiesis and, in cooperation with secondary mutations, leads to the development of leukemia. Most t(8;21) patients treated with current therapies who achieve hematological and cytogenetic long-term remission retain AML1-ETO transcripts in their bone marrow which are produced from either leukemic or preleukemic cells that were not eradicated. Thus, although 90% of patients achieve complete remission, 35-40% of these patients relapse within five years due to the resurgence of residual t(8;21) expressing cells. We hypothesize that direct therapeutic targeting of the AML1-ETO protein may reduce the rate of relapse and improve the long- term survival of these patients. We plan to specifically inhibit the activity of the AML1-ETO protein with small molecules. To this end, we have shown that the AML1-ETO:CBF2 interaction is essential for AML1-ETO's leukemogenic and pre- leukemogenic activity. We have begun to develop small molecule inhibitors of the AML1-ETO:CBF2 interaction using structure-based and high throughput screens and well-validated assays. We are employing medicinal chemistry to optimize these leads. We also plan to develop homodimeric and heterodimeric inhibitors from the small molecules that will have selectivity for AML1-ETO versus Runx1 (AML1). All inhibitors will be tested for their activity on mouse and leukemia cell lines, on normal bone marrow cells, and in mouse models for t(8;21) leukemia.

描述（由申请人提供）：编码RUNX1（AML1）的基因被t（8; 21）与人类中约12％的急性髓样白血病有关。 t（8; 21）导致产生含有Runx1的N端的融合蛋白，包括Runt结构域，几乎与所有ETO融合在一起。 AML1-Eto融合蛋白充当核心结合因子功能的主要阻遏物，使正常造血所需的多个基因的表达失调，并与继发突变合作导致白血病的发展。大多数T（8; 21）患者接受了当前疗法治疗的患者，这些疗法获得了血液学和细胞遗传学长期缓解的骨髓中的AML1-ETO转录本，这些转录本是由白血病或未消除的白血病或蓬利血症细胞产生的。因此，尽管有90％的患者已完全缓解，但由于残留t（8; 21）表达细胞的复发，这些患者中有35-40％在五年内复发。我们假设AML1-Eto蛋白的直接治疗靶向可以降低复发率并改善这些患者的长期存活率。 我们计划特别抑制与小分子的AML1-Eto蛋白的活性。为此，我们表明AML1-ETO：CBF2相互作用对于AML1-Eto的白血病和白细胞前活性至关重要。我们已经开始使用基于结构和高吞吐量筛选以及验证良好的测定法开发AML1-Eto：CBF2相互作用的小分子抑制剂。我们正在采用药物化学来优化这些铅。我们还计划从小分子中开发同二聚体和异二二聚体抑制剂，这些抑制剂将对AML1-ETO与RunX1（AML1）具有选择性。将测试所有抑制剂在小鼠和白血病细胞系，正常骨髓细胞以及T（8; 21）白血病的小鼠模型中的活性。