Design of Potent Menin–KMT2A Interaction Inhibitors\nwith Improved <i>In Vitro</i> ADME Properties and Reduced\nhERG Affinity

Inhibitors\nof the interaction of menin (MEN1) with lysine methyltransferase\n2A (KMT2A) have emerged as novel therapeutic options in the treatment\nof genetically defined acute leukemias. Herein, we describe the structure-based\ndesign, synthesis, and biological evaluation of novel inhibitors of\nthe menin–KMT2A interaction. Our structure–activity\nrelationship campaign focused on achieving high antiproliferative\ncellular activity while mitigating risks associated with CYP3A4-dependent\nmetabolism and hERG inhibition, which were characterized in some early\nclinical candidates. Our efforts resulted in the discovery of a triazine-based\ncompound series that inhibited MV4-11 leukemia cell line proliferation\nwith IC<sub>50</sub> as low as 13 nM, and selected compounds demonstrated\nimproved <i>in vitro</i> ADME properties, de-risked CYP3A4\ndependency, and lower hERG inhibition.