The Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

The receptor tyrosine kinase EPHA2 has gained interest as therapeutic drug target in cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small molecule inhibitors. Here, we report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as a lead structure. We designed hybrid structures of Dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955 and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2. Medicinal chemistry and inhibitor design was guided by a chemical proteomic approach allowing for early selectivity profiling of the newly synthesized inhibitor candidates. Concomitant protein crystallography of 17 inhibitor co-crystals delivered detailed insight into the atomic interactions that underlie the structure-affinity-relationship. Finally, the antiproliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we thus discovered a novel EPHA2 inhibitor candidate 4a featuring an improved selectivity profile while maintaining potency against EPHA2 and anti-cancer activity in SF-268 cells.