The MYC family of cellular oncogenes encodes three highly related nuclear phosphoproteins (c-Myc, N-Myc, and L-Myc) that are believed to function as sequence-specific transcription factors capable of regulating genes important in cellular growth and differentiation.  Due to this involvement in central cellular processes they play a key role in development and maintenance of a multitude of human cancer diseases. Cellular MYC concentration is tightly regulated at the level of protein stability through canonical upstream kinase signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), cyclin-dependent kinase 2 (CDK2), and mitogen-activated protein kinase (MAPK). These kinases direct sequential phosphorylation and dephosphorylation of conserved residues in MYC proteins, which target them for ubiquitination followed by proteasomal degradation.  Gustafson et al. showed in 2014 that Aurora Kinase A protects N-MYC against degradation by forming a protein-protein-interaction. This stabilization was interrupted by conformation disrupting inhibitors not acting like classical type I Kinase inhibitors. Additionally, Dauch et al. produced similar results for c-MYC, after siRNA-screens detected an increased Aurora Kinase A levels in a MYC-dependent hepatocellular carcinoma cell line, confirming that appropriate inhibitors show the desired biological effect. In-silico-modelling showed a possible explanation for the observed biological effects of conformation disrupting inhibitors. Aurora Kinase A seems to mask phosphor-residues that target MYC for ubiquitination, subsequent preventing formation of the MYC/Aurora complex should result in proteasomal degradation of MYC (fig. 1). 
Our studies focus on design and synthesis of decent Aurora Kinase A inhibitors providing structural features that are able to prevent complex formation to ultimately achieve the degradation of MYC - a target, that is considered undruggable.
Figure 1: Schematic mode of action; left: Type-I-Inhibitors enable the interaction between phosphorylated c‑MYC; middle: conformation-disrupting-Inhibitors suppress formation of the protein-protein-complex; right: already built complexes are not affected. 
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