Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

Histone methyltransferase DOT1L is an attractivetherapeutic target for the treatment of hematological malignancies.Here, we report the design, synthesis, and profiling of new DOT1Linhibitors based on nonroutine carbocyclic C-nucleoside scaffolds.The experimentally observed SAR was found to be nontrivial asseemingly minor changes of individual substituents resulted insignificant changes in the affinity to DOT1L. Molecular modelingsuggested that these trends could be related to significantconformational changes of the protein upon interaction with theinhibitors. The compounds22and (-)-53(MU1656), carbocyclicC-nucleoside analogues of the natural nucleoside derivativeEPZ004777, and the clinical candidateEPZ5676(pinometostat)potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compoundMU1656was found to be moremetabolically stable and significantly less toxic in vivo than pinometostat itself.