Discovery of Novel, Potent, and Selective Small-Molecule Menin–Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin–mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin–MLL interaction inhibitors with potent binding affinity and improved physical properties.