Abstract
Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.
Highlights
We investigated the impact of the inhibition of H3K79me2 in MLLr cells on the expression of the pro-leukemic genes, HOXA9 and MEIS1
The efficacy of Dia2 is comparable to EPZ-5676. These results, together with the inhibition of MLLr cell proliferation are encouraging, and we studied the effect of the compound on the cell cycle and apoptosis
DOT1L has emerged as an attractive therapeutic target in MLLr
Summary
Epigenetic chemical modifications constitute a dynamic system and play a major role in normal cell development and differentiation. These epigenetic modifications have been found to be altered in several diseases such as cancer [2]. Among these modifications, the dynamic methylation of nucleosomal histones represents a complex code that will open or compact chromatin depending on the number of methyl groups (mono, di or trimethylation, symmetric or asymmetric methylation), the context (other marks on the histones and DNA) and the localization on the histones [3]
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