However, aureolic acid drugs regained attention drastically in 2011 after MTM was found in an NCI screening to be the only hit out of 50,000 compounds to affect Ewing sarcoma transcription factors, previously believed to be ’undruggable’. Ewing sarcomas are a rare bone cancer affecting children and young adults, and used to be untreatable for more than 40 years.
Biosynthetic investigations of the MTM pathway paved the way to generate new MTM derivatives with promising properties. First and second generation analogues were prepared by combinatorial biosynthetic approaches, while most promising third generation-MTM analogues were prepared chemo-enzymatically. How these newest MTM-derivatives act and were crucial to deduce a novel hypothesis of MTM’s mechanism-of-action against Ewing sarcoma will be outlined.