A Medicinal Chemistry Perspective for Targeting Histone H3 Lysine-79 Methyltransferase DOT1L

Abstract

Histone H3 lysine79 (H3K79) methyltransferase DOT1L plays an important role in the activation and maintenance of gene transcription. It is essential for embryonic development as well as normal functions of the hematopoietic system, heart and kidney in adults. DOT1L has been found to be a drug target for acute leukemia with mixed lineage leukemia (MLL) gene translocations. The rearranged onco-MLL can recruit DOT1L, causing aberrant H3K79 methylation, overexpression of leukemia relevant genes, and eventually leukemogenesis. Potent DOT1L inhibitors possess selective activity against this type of leukemia in cell-based and animal studies, with the most advanced compound being in clinical trials. In the medicinal chemistry point of view, we review the biochemistry, cancer biology and current inhibitors of DOT1L, as well as biophysical (including X-ray crystallographic) investigation of DOT1L-inhibitor interactions. Potential future directions in the context of drug discovery and development targeting DOT1L are discussed.

Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications

“…DOT1L has also been found to be associated with mixed lineage leukemia (MLL) fusion proteins, resulting in aberrant methylation patterns of H3K79 and dysregulation of MLL targeted genes (Okada et al 2005). Clinical trials are currently underway using DOT1L-targeting drugs in MLL (Anglin and Song 2013). Methylation of H4K20 is regulated by the PR-SET7 methyltransferase in a cell cycle-dependent manner (Nishioka et al 2002), and these modifications have been shown to play a role in DNA damage responses by attracting TP53BP1 (Beck et al 2012).…”

Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond

“…3A–C) [150]. The first three segments are consensus sequence motifs also found on other SAM-dependent methyltransferases, whereas the last two segments are unique to DOT1L [151]. Additionally, a flexible and positively charged region between amino acid residues 390 and 407 is critical for nucleosome/DNA binding and methyltransferase activity [150].…”

“…However, SAH inhibits binding of the cofactor SAM to most of the SAM-dependent methyltransferases [151]. In 2011, the first-in-class aminonucleoside-based DOT1L specific inhibitor EPZ004777 that selectively suppresses leukemia cells with MLL1 translocations was identified (Fig.…”

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

“…They have developed a small molecule inhibitor EPZ-5676, which is currently the first and only inhibitor that has entered clinical trials for the treatment of MLL-rearranged leukemia [27]. EPZ-5676, together with hundreds of other inhibitors developed by Epizyme, was identified by the classic ligandbased design and the following painstaking work of optimization [28][29][30]. As a result, all inhibitors derived from the S-adenosyl-L-homocysteine (SAH) contain the adenosine-like moiety which can be easily targeted and decomposed by endogenous enzymes.…”