Disruption of protein-protein interactions is a promising therapeutic alternative in the field of oncology. Here, we disclose the discovery of a series able to disrupt the interaction of the transcription factor RunX1 with its activator core binding factor beta (CBFβ). This interaction is at the core mechanism of driving Acute Myeloid Leukemia Subtype M4Eo. The molecules described in this report, exemplified by ML223, show activity in relevant cell, zebra fish and mouse models, and are currently being considered for further drug development.