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

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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.