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

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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.