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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的长期目标是了解MLL(混合血统白血病)融合蛋白诱导白血病发生的分子机制，并开发干预白血病发生所需生物过程的小分子化合物。MLL基因是人类急性白血病(1-4)染色体易位的常见靶点，最近的研究表明，与MLL融合的进化保守的CBP的溴域(BRD)和组蛋白乙酰转移酶(HAT)结构域是发生急性髓系白血病(AML)(3，4)的最低必要条件和充分条件。利用基于核磁共振结构的方法，我们小组开发了具有高亲和力和选择性的小分子抑制剂，这些小分子抑制剂干扰细胞内CBP BRD的生物学功能(5，6)。此外，我对该络合物的计算研究提供了一种能量和动态的选择性描述，导致设计出一种可能比原始化合物具有更高亲和力的新分子(S)。在对CBP BRD的配体特异性有了新的认识的基础上，我们建议利用计算方法结合核磁共振结构研究来开发新的具有高亲和力的高选择性配体作为CBP功能的有效抑制剂。这些化学配体将作为强有力的工具研究MLL-CBP诱导AML的机制，并验证CBP BRD作为治疗AML的新靶点。这一模型系统研究的新结果对于理解MLL诱导白血病发生的一般分子基础以及开发和测试潜在的治疗药物也应该具有广泛的意义。

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.