Tag: M.W=500-550

Niwa, Hitoshi published the artcileA Stepping Stone to Pluripotency, Synthetic Route of 1338466-77-5, the publication is Cell (Cambridge, MA, United States) (2015), 163(7), 1570-1572, database is CAplus and MEDLINE.

A review. The research of Y. Zhao et al. (ibid., 1678-91) is reviewed with commentary and references Somatic cells can be reprogrammed into pluripotent stem cells via either expression of transcription factors or addition of small mol. chems. only. Zhao et al. reveal a unique intermediate state during chem. reprogramming allowing a significant improvement in its efficiency and kinetics.

Cell (Cambridge, MA, United States) published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Synthetic Route of 1338466-77-5.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Zhao, Yang published the artcileA XEN-like state bridges somatic cells to pluripotency during chemical reprogramming, Recommanded Product: 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, the publication is Cell (Cambridge, MA, United States) (2015), 163(7), 1678-1691, database is CAplus and MEDLINE.

Somatic cells can be reprogrammed into pluripotent stem cells (PSCs) by using pure chems., providing a different paradigm to study somatic reprogramming. However, the cell fate dynamics and mol. events that occur during the chem. reprogramming process remain unclear. Here, the authors show that the chem. reprogramming process requires the early formation of extra-embryonic endoderm (XEN)-like cells and a late transition from XEN-like cells to chem.-induced (Ci)PSCs, a unique route that fundamentally differs from the pathway of transcription factor-induced reprogramming. Moreover, precise manipulation of the cell fate transition in a step-wise manner through the XEN-like state allowed the authors to identify small-mol. boosters and establish a robust chem. reprogramming system with a yield up to 1000-fold greater than that of the previously reported protocol. These findings demonstrate that chem. reprogramming is a promising approach to manipulate cell fates.

Cell (Cambridge, MA, United States) published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C24H20Ge, Recommanded Product: 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Tao, Jia published the artcileDOT1L inhibitor improves early development of porcine somatic cell nuclear transfer embryos, Recommanded Product: 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, the publication is PLoS One (2017), 12(6), e0179436/1-e0179436/12, database is CAplus and MEDLINE.

Incomplete epigenetic reprogramming of the genome of donor cells causes poor early and full-term developmental efficiency of somatic cell nuclear transfer (SCNT) embryos. Previous research indicate that inhibition of the histone H3 K79 methyltransferase DOT1L, using a selective pharmacol. inhibitor EPZ004777 (EPZ), significantly improved reprogramming efficiency during the generation of mouse induced pluripotent stem cells. However, the roles of DOT1L in porcine nuclear transfer-mediated cellular reprogramming are not yet known. Here we showed that DOT1L inhibition via 0.5 nM EPZ treatment for 12 or 24 h significantly enhanced the blastocyst rate of SCNT embryos and dramatically reduced the level of H3K79me2 during SCNT 1-cell embryonic development. Addnl., H3K79me2 level in the EPZ-treated SCNT embryos was similar to that in in vitro fertilized embryos, suggesting that DOT1L-mediated H3K79me2 is a reprogramming barrier to early development of porcine SCNT embryos. qRT-PCR anal. further demonstrated that DOT1L inactivation did not change the expression levels of DOT1L itself but increased the expression levels of POU5F1, LIN28, SOX2, CDX2 and GATA4 associated with pluripotency and early cell differentiation. In conclusion, DOT1L inhibitor improved early developmental efficiency of porcine SCNT embryos probably via inducing the increased expression of genes important for pluripotency and lineage specification.

PLoS One published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C13H9FO2, Recommanded Product: 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Chen, Huifang published the artcileCross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer, Formula: C28H41N7O4, the publication is Molecular Cancer (2021), 20(1), 29, database is CAplus and MEDLINE.

The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer”enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these “writer”; in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. We systematically characterized mRNA expression and genetic alterations of 26 RNA modification “writer” in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification “writer”. Subsequently, we constructed the RNA modification “writer”; Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association anal. for WM_Score and characteristics of TME, consensus mol. subtypes (CMSs), clin. features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. We demonstrated that multi-layer alterations of RNA modification”writer” are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly neg. correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, pos. correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these “writer”to aid the clin. benefits of immunotherapy. Our study is the first to provide a comprehensive anal. of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clin. utility of RNA modification “writer”in cancer therapy.

Molecular Cancer published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Formula: C28H41N7O4.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Yu, Wenyu published the artcileBromo-deaza-SAH: A potent and selective DOT1L inhibitor, Application of 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, the publication is Bioorganic & Medicinal Chemistry (2013), 21(7), 1787-1794, database is CAplus and MEDLINE.

Chem. inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacol. inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chem. of DOT1L inhibition would accelerate the development of improved compounds Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clin. candidates against mixed lineage leukemia.

Bioorganic & Medicinal Chemistry published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C7H7IN2O, Application of 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Niu, Ningning published the artcileBromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth, Product Details of C28H41N7O4, the publication is Journal of Biological Chemistry (2016), 291(52), 26647-26657, database is CAplus and MEDLINE.

Small mol. inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clin. trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1. Furthermore, we constructed a zebrafish line in which the enhanced green fluorescent protein (EGFP) expression was driven by col2a1 promoter. The transgenic (col2a1-EGFP) zebrafish line demonstrated that BET inhibitors I-BET151 and (+)-JQ1 may affect EGFP expression in zebrafish. Furthermore, we found that I-BET151 and (+)-JQ1 may affect chondrocyte differentiation in vitro and inhibit zebrafish growth in vivo. Mechanistic anal. revealed that BET inhibitors influenced the depletion of RNA polymerase II from the Col2a1 promoter. Collectively, these results suggest that BET bromodomain inhibition may have side effects on skeletal bone structures.

Journal of Biological Chemistry published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Product Details of C28H41N7O4.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Premkumar, Kavitha published the artcileIdentification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds, Computed Properties of 1338466-77-5, the publication is Life Sciences (2022), 120643, database is CAplus and MEDLINE.

Regulatory T cells play an essential role in immune tolerance and homeostasis. Their long-term stability depends on epigenetic modifications and identification of small mol. modulators of Treg differentiation therefore has many applications. In this study, we performed a novel functional screen of an epigenetic compound library to identify compounds that can modulate generation of TGF-β1 induced T regulatory cells. A screening strategy based on IFN-γ ELISA was designed to screen epigenetic compound library. Effect of hit compounds on Treg phenotype and function was assessed by RT-PCR, flow cytometry and suppression assays. TGF-β signalling proteins were assayed by western blotting. Chromatin Immunoprecipitation (ChIP) assay was used to assess epigenetic modifications at Foxp3 gene locus. We screened 160 compounds to identify hits capable of reversing TGF-β induced inhibition of IFN-γ production in activated spleen cells and CD4+ T cells. Two compounds EPZ004777 and FG-2216 consistently reversed TGF-β1 iTregs in terms of (a) differentiation of naive T cells into CD4+CD25+Foxp3+Treg cells, (b) Foxp3 target gene expression and (c) Treg suppressive function without affecting TGF-β downstream signalling. ChIP assay revealed that the compounds were able to reverse – TGF- β mediated decrease in epigenetic marks H3K27me3 and 5-mC and an increase in epigenetic marks H3K4me3 and H3K27Ac in the promoter and conserved non coding sequence (CNS1) regions of the Foxp3 gene. EPZ004777 and FG-2216 have been identified as potent epigenetic modulators that can reverse TGF-β1 induced T regulatory cells and may be used to treat diverse immune disorders.

Life Sciences published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Computed Properties of 1338466-77-5.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Khirsariya, Prashant published the artcileSynthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides, Safety of 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, the publication is Journal of Medicinal Chemistry (2022), 65(7), 5701-5723, database is CAplus and MEDLINE.

Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematol. malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The exptl. observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Mol. modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (-)-53 (MU1656), carbocyclic C-nucleoside analogs of the natural nucleoside derivative EPZ004777, and the clin. candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.

Journal of Medicinal Chemistry published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Safety of 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Gibbons, Garrett S. published the artcileRegulation of Wnt Signaling Target Gene Expression by the Histone Methyltransferase DOT1L, Formula: C28H41N7O4, the publication is ACS Chemical Biology (2015), 10(1), 109-114, database is CAplus and MEDLINE.

The histone methyltransferase DOT1L, solely responsible for histone H3 lysine 79 (H3K79) methylation, is associated with gene activation. Human leukemias carrying MLL gene rearrangements aberrantly recruit DOT1L to leukemogenic genes leading to increased H3K79 methylation and their transcriptional activation. Recent studies suggest that Wnt-targeted genes also depend on H3K79 methylation. Employing a chem. biol. approach, the requirement for H3K79 methylation was investigated in Wnt pathway-inducible HEK293 cells and human colon adenocarcinoma-derived cell lines by inhibiting DOT1L with EPZ004777, a selective and potent S-adenosylmethionine competitive inhibitor. Our findings indicate that H3K79 methylation is not essential for the canonical Wnt signaling pathway, in particular for maintenance or activation of Wnt pathway target gene expression. Furthermore, H3K79 methylation is not elevated in human colon carcinoma samples in comparison with normal colon tissue. Therefore, our findings indicate that inhibition of DOT1L histone methyltransferase activity is likely not a viable therapeutic strategy in colon cancer.

ACS Chemical Biology published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Formula: C28H41N7O4.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem

Daigle, Scott R. published the artcileSelective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor, Category: tetrahydrofurans, the publication is Cancer Cell (2011), 20(1), 53-65, database is CAplus and MEDLINE.

Mislocated enzymic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.

Cancer Cell published new progress about 1338466-77-5. 1338466-77-5 belongs to tetrahydrofurans, auxiliary class Epigenetics,Histone Methyltransferase, name is 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)urea, and the molecular formula is C28H41N7O4, Category: tetrahydrofurans.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydrofuran,
Tetrahydrofuran | (CH2)3CH2O – PubChem