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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
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 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
Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase.
TLDR
CP-358,774 has potential for the treatment of tumors that are dependent on the EGFR pathway for proliferation or survival and triggers apoptosis in these cells as determined by formation of DNA fragments and other criteria. Expand
Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2
TLDR
Treatment of SMARCB1 mutant MRTs with a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity leads to dose-dependent regression of MRT's with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. 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
Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma
TLDR
Activity of EPZ-6438 is characterized in preclinical models of NHL to confirm the dependency of EZH2-mutant NHL on EzH2 activity and portend the utility ofEPZ- 6438 as a potential treatment for these genetically defined cancers. 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
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
Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.
TLDR
GSK3368715 is described, a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models and deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioADenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK 3368715 in cell lines. Expand
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