NOVEL SMALL MOLECULES FOR INVESTIGATING MECHANISMS OF MLL-CBP-INDUCED LEUKEMIA

用于研究 MLL-CBP 诱发白血病机制的新型小分子

• 批准号: 7601479
• 负责人: YOEL RODRIGUEZ
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601479
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Affinity; Biological Models; Biological Process; Bromodomain; Cells; Chemicals; Chimeric Proteins; Chromosomal translocation; Complex; Computer Retrieval of Information on Scientific Projects Database; Funding; Goals; Grant; Human; Institution; Ligands; MLL gene; Molecular; Research; Research Personnel; Resources; Source; Specificity; Structure; Testing; Therapeutic Agents; United States National Institutes of Health; base; computer studies; design; histone acetyltransferase; inhibitor/antagonist; leukemia; leukemogenesis; novel; novel therapeutics; small molecule; therapeutic target; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to understand the molecular mechanisms of leukemogenesis induced by MLL (mixed-lineage leukemia) fusion proteins and to develop small-molecule chemical compounds that intervene in the biological processes required for leukemogenesis. The MLL gene is a common target for chromosomal translocations associated human acute leukemias (1-4) and recent studies show that the evolutionarily conserved bromodomain (BRD) and histone acetyltransferase (HAT) domain of the co-activator CBP fused to MLL are minimally necessary and sufficient for developing acute myeloid leukemia (AML) (3, 4). Using NMR structure-based approach our group developed small-molecule inhibitors with high affinity and selectivity that interfere with the biological function of the CBP BRD in cells (5, 6). Furthermore, my computational studies of the complex provided an energetic and dynamic description of the selectivity leading to the design of a new molecule(s) with potentially higher affinity than the original compound. On the basis of the new understanding of ligand specificity of the CBP BRD, we propose to use computational approaches along with NMR structural studies to develop new highly selective ligands with high affinity as effective inhibitors of CBP function. These chemical ligands will be used as powerful tools to investigate the mechanisms of MLL-CBP-induced AML, and to validate the CBP BRD as a new therapeutic target for AML treatment. The emerging results from this model system study should also have broad implications for understanding the molecular basis of MLL-induced leukemogenesis in general and for developing and testing potential therapeutic agents.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的长期目标是了解由MLL（混合谱系白血病）融合蛋白诱导的白血病发生的分子机制，并开发干预白血病发生所需的生物过程的小分子化合物。MLL基因是染色体易位相关的人急性白血病的常见靶标（1-4），最近的研究表明，与MLL融合的共激活因子CBP的进化上保守的布罗莫结构域（BRD）和组蛋白乙酰转移酶（HAT）结构域对于发展急性髓性白血病（AML）是最低限度必需和足够的（3，4）。使用基于NMR结构的方法，我们的团队开发了具有高亲和力和选择性的小分子抑制剂，其干扰细胞中CBP BRD的生物学功能（5，6）。此外，我对复合物的计算研究提供了对选择性的充满活力和动态描述，从而设计出比原始化合物具有潜在更高亲和力的新分子。基于对CBP BRD配体特异性的新认识，我们建议使用计算方法沿着NMR结构研究来开发具有高亲和力的新的高选择性配体作为CBP功能的有效抑制剂。这些化学配体将被用作研究MLL-CBP诱导AML的机制的有力工具，并验证CBP BRD作为AML治疗的新靶点。该模型系统研究的新结果对于理解MLL诱导的白血病发生的分子基础以及开发和测试潜在的治疗药物也具有广泛的意义。