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

靶向转录因子 c-Myb 来治疗急性髓系白血病 (AML)

• 批准号: 440373522
• 负责人: Dr. Jasmin Krüll
• 金额: --
• 依托单位: Koehler Lab
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/440373522?language=en
• 关键词: Targeting; transcription; factor; Myb; address

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.

细胞过程的调节，如生殖，对人类有机体至关重要。为了确保这些过程的受控性能，由相互作用的蛋白质组成的不同信号级联是至关重要的。级联反应的最后一个相互作用蛋白通常是一个转录因子，它可以与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。考虑到急性髓细胞白血病（AML），检测到转录因子c-Myb的过度活性。c-Myb与辅激活蛋白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。因此，应防止c-Myb与CBP/p300以及TF IID的相互作用。CBP/p300的KIX结构域和TF IID的TAD 12亚结构域是c-Myb-KIX相互作用的主要抑制剂，但迄今为止，还没有发现有希望抑制c-Myb-KIX相互作用的化合物。在此基础上，提出了基于KIX结构域的靶结构，该结构域与c-Myb结合而不是与CBP/p300结合，并由主持人Angela Koehler教授领导的研究小组高通量筛选了阻断c-Myb与TAD 12相互作用的靶结构。这一结构应被视为本提案的出发点，并进一步优化。在目标结构合成后，这些化合物的生物评价应进行优化和应用。应根据生物学评价的结果提出改进的靶结构，之后还应进行测试。