A series of lead structures identified from a High Throughput Screen (HTS) targeting the Menin-Mixed Lineage Leukemia (MLL) protein-protein interaction are reported. Two chemical series have been prosecuted to date and one piperidine series was identified to have tractable and rapidly response Structure Activity Relationship (SAR) affording inhibitors of the Menin-MLL interaction with sub-micromolar inhibitory activity. Moreover, preliminary data suggests these compounds display activity in cellular systems relevant to understanding the Menin-MLL pathway and the disease progression. SAR and characterization of the declared probe ML227 from this effort are described.