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Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
TLDR
In vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model, providing compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. Expand
Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas
TLDR
The results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZh1) together with the mutant PRC2s for augmented conversion of H3k27 to the trimethylated form. Expand
Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases.
TLDR
It is shown that rapid progestin-induced activation of Src and downstream MAP kinase in mammalian cells is dependent on PR-SH3 domain interaction, but not on the transcriptional activity of PR. Expand
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.
TLDR
The discovery of EPZ005687 is reported, a potent inhibitor of EZH2 that reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. Expand
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
TLDR
The characterization of EPZ-5676 is described, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity that demonstrates 37 000-fold selectivity over all other methyltransferases tested. Expand
A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.
TLDR
EPZ015666 is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Expand
A687V EZH2 is a gain‐of‐function mutation found in lymphoma patients
TLDR
Another EZH2 SET domain point mutation, A687V, occurring in about 1–2% of lymphoma patients, is shown to be a gain‐of‐function mutation that greatly enhances its ability to perform dimethylation relative to wild‐type EZh2 and is equally proficient at catalyzing trimethylation. Expand
Studies on the induction of rat hepatic CYP1A, CYP2B, CYP3A and CYP4A subfamily form mRNAs in vivo and in vitro using precision-cut rat liver slices
TLDR
Real-time quantitative reverse transcription-polymerase chain reaction methodology (TaqMan®) was used to examine the induction of some selected rat hepatic cyto-chrome P450 (CYP) forms in vivo and in vitro using cultured precision-cut liver slices and found the magnitude of induction of CYP mRNA levels was greater after 24 h in liver slices cultured in DeX-free than in DEX-supplemented medium. Expand
Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L
TLDR
It is found that improvements in target enzyme affinity and selectivity are driven entirely by diminution of the dissociation rate constant for the enzyme–inhibitor complex, leading to long residence times for the binary complex. Expand
Chemogenetic Analysis of Human Protein Methyltransferases
TLDR
A survey of the human genome was performed to understand the constituency of protein methyltransferases and the relatedness of their catalytic domains and it is shown that a representative METTL, METTL11A, demonstrates catalytic activity as a histone methyltransferase. Expand
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