Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L.

Histone methyltransferase DOT1L is a drug target for MLL leukemia. We report an efficient synthesis of a cyclopentane-containing compound that potently and selectively inhibits DOT1L (K _i = 1.1 nM) as well as H3K79 methylation (IC ₅₀ ~ 200 nM). Importantly, this compound exhibits a high stability in plasma and liver microsomes, suggesting it is a better drug candidate.