Targeting the transcription factor c-Myb to address acute myeloid leukemia (AML)

对生殖等细胞过程的调节对人类有机体是必不可少的。为了确保这些过程的可控性能，由相互作用的蛋白质组成的多种信号级联是至关重要的。级联的最后一个相互作用的蛋白质通常是一个转录因子，它可能与DNA相互作用，从而编码它们的信息。任何蛋白质的失调都可能导致癌症等疾病。考虑到急性髓性白血病（AML），检测到转录因子c-Myb的过度活性。c-Myb与协同激活蛋白CBP/p300和转录因子IID （TF IID）之间的相互作用被证明是高度相关的。该建议的目的是使用不同的方法来针对“反洗钱”。因此，应防止c-Myb与CBP/p300以及TF IID的相互作用。更详细地说，CBP/p300的kix结构域和TF IID的tad12子结构域负责结合。到目前为止，还没有发现有希望抑制c- myb - kix相互作用的化合物。在本提案的范围内，提出了基于kix结构域的目标结构，该结构应该结合c-Myb而不是CBP/p300。主持Angela Koehler教授课题组对中断c-Myb与TAD12相互作用的hit结构进行了高通量筛选。应将此结构作为本方案的出发点，并进一步优化。在目标结构合成后，对这些化合物进行生物学评价优化和应用。应根据生物学评价的结果提出改进的靶结构，然后也应进行测试。

A regulation of cell processes such as reproduction is essential for human organisms. To ensure a controlled performance of these processes, diverse signal cascades consiting of interacting proteins are of utmost importance. The last interacting protein of the cascade is usually a transcription factor which may interact with DNA and thus, encode their information. Dysregulations of any protein can lead to diseases such as cancer.Considering acute myeloid leukemia (AML) an overactivity of the transcription factor c-Myb was detected. The interactions between c-Myb and the Co-activator protein CBP/p300 and the transcription factor IID (TF IID) turned out to be of high relevance.The aim of this proposal is to target AML using different approaches. Therefore, the interaction of c-Myb to CBP/p300 as well as to TF IID should be prevented. In more detail, the KIX-domain of CBP/p300 and the TAD12-subdomain of TF IID are responsible for the binding.Until now, no promising compounds for the inhibition of the c-Myb-KIX-interaction had been discovered. Within the scope of this proposal, target structures based on the KIX-domain were proposed which should bind to c-Myb instead of CBP/p300.Furthermore, led a high-throughput screening by the research group of the host Prof. Angela Koehler to the hit structure which interrupts the interaction between c-Myb and TAD12. This structure should be considered as starting point for this proposal and be further optimized.After the syntheses of the target structures, a biological evaluation of these compounds should be optimized and applied. Improved target structures should be proposed based on the results of the biological evaluation and should afterwards also be tested.