Summary activity statement /

ML227 (CID 46926632, SID 99432383) is a non-covalent inhibitor of the menin-MLL interaction. ML227 can be accessed synthetically in three-four steps in good overall yield. ML227 shows excellent inhibition in the HTRF assay and demonstrates moderate inhibition on cell proliferation in MLL leukemia cells harboring different translocations of MLL, including: MV4;11 (harboring MLL-AF4 fusion protein), ML-2 (with MLL-AF6 fusion protein) and KOPN-8 (with MLL-ENL fusion protein). ML227 is anticipated to lead to further interest in the development of small molecule inhibitors for the treatment of MLL associated leukemias. ML227 represents the first Menin-Mixed Lineage Leukemia (MLL) small molecule protein-protein interaction inhibitor with sub-micromolar inhibitory activity. This probe will be used by the research community to further elucidate the importance of the menin-MLL interaction in MLL-mediated leukemogenesis and offers a potential drug discovery path to develop small molecules to treat acute lymphoid and myeloid leukemias with MLL rearrangements Translocations of MLL result in acute leukemias with poor prognosis and development of novel therapeutic strategies is highly desired. Leukemogenic activity of MLL fusion proteins is dependent of their interactions with menin, validating the importance of this interaction as a potential drug target for leukemia (Yokoyama 2005, Caslini 2007). Currently, peptide fragments have been identified which are reported to be efficacious in disrupting the Menin-MLL interactions in vitro and in cells (Caslini 2007, Hess 2011). Although development of small peptide disruptors is generally useful for mapping features of the active binding surface and as probes for screening purposes, these tools are typically not viable as lead starting points for small molecule drug discovery. In light of the compelling evidence to date identifying the Menin-MLL fusion protein interaction as a rate limiting interaction necessary for leukemic cell proliferation and blockage of hematopoietic differentiation, the community is earnestly searching for small molecules to disrupt and block the Menin-MLL mediated pathway (Hess 2011). In addition to utilizing a probe molecule to further validate the molecular target, we are focused on identifying good probe compounds to serve as leads for further lead development within the context of the extended probe mechanism. Such compounds might result in novel targeted therapies for MLL-associated acute leukemias, and could also be used a chemical probes to study the biology of MLL and MLL fusion protein mediated leukemogenesis.