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Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149185 | GEO | 2020/06/01

REPOSITORIES: GEO

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Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (RNA-seq dataset)

Project description:Using 3-end RNA-seq followed by digital gene expression analyses we assessed genes that change expression upon treatment with the DOT1L-methyltransferase inhibitors EPZ5676 and the novel drug "compound 10"

2020-06-01 | GSE149184 | GEO

Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (ChIP-seq dataset)

Project description:using ChIP-seq we examined Chromatin occupancy of the MLL-fusion complex members Menin and DOT1L after treatment with DOT1L methyltransferase inhibitors EPZ5676 and the novel compounds "compound 10" and "compound 11" as well as with the Menin-inhibitor VTP50469 in MOLM13 cells. Furthermore we used ChiP-seq to quantify the loss of H3K79me2 (histone mark deposited by DOT1L) after treatment with the DOT1L inhibitors EPZ5676 and "compound 10" in MOLM13 and RS4,11 cells.

2020-06-01 | GSE149183 | GEO

Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts

Project description:Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts

| PRJNA627609 | ENA

Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (RNA-seq dataset)

Project description:Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (RNA-seq dataset)

| PRJNA627611 | ENA

Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (ChIP-seq dataset)

Project description:Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (ChIP-seq dataset)

| PRJNA627612 | ENA

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation.

Project description:Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.

| S-EPMC4724257 | biostudies-literature

Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L.

Project description:Histone methyltransferase DOT1L is a drug target for MLL leukemia. We report an efficient synthesis of a cyclopentane-containing compound that potently and selectively inhibits DOT1L (Ki = 1.1 nM) as well as H3K79 methylation (IC50 ~ 200 nM). Importantly, this compound exhibits a high stability in plasma and liver microsomes, suggesting it is a better drug candidate.

| S-EPMC3686528 | biostudies-literature

Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L.

Project description:Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC(50) values of 4-11 ?M. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine) but not the substrate nucleosome.

| S-EPMC3475323 | biostudies-literature

Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Project description:Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.

| S-EPMC5346981 | biostudies-literature

Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies.

Project description:Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.

| S-EPMC3492951 | biostudies-literature

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