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LSD1 inhibitor

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https://www.readbyqxmd.com/read/29787289/trends-of-lsd1-inhibitors-in-viral-infections
#1
Clemens Zwergel, Giulia Stazi, Antonello Mai, Sergio Valente
No abstract text is available yet for this article.
May 22, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29765516/selective-dissociation-between-lsd1-and-gfi1b-by-a-lsd1-inhibitor-ncd38-induces-the-activation-of-erg-super-enhancer-in-erythroleukemia-cells
#2
Ryusuke Yamamoto, Masahiro Kawahara, Shinji Ito, Junko Satoh, Goichi Tatsumi, Masakatsu Hishizawa, Takayoshi Suzuki, Akira Andoh
Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29707403/histone-demethylase-lsd1-regulates-bone-mass-by-controlling-wnt7b-and-bmp2-signaling-in-osteoblasts
#3
Jun Sun, Joerg Ermann, Ningning Niu, Guang Yan, Yang Yang, Yujiang Shi, Weiguo Zou
Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2...
2018: Bone Research
https://www.readbyqxmd.com/read/29593255/stress-induced-phosphoprotein-1-acts-as-a-scaffold-protein-for-glycogen-synthase-kinase-3-beta-mediated-phosphorylation-of-lysine-specific-demethylase-1
#4
Chia-Lung Tsai, An-Shine Chao, Shih-Ming Jung, Chiao-Yun Lin, Angel Chao, Tzu-Hao Wang
Stress-induced phosphoprotein 1 (STIP1)-a co-chaperone of heat shock proteins-promotes cell proliferation and may act as an oncogenic factor. Similarly, glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of lysine-specific demethylase 1 (LSD1)-an epigenetic regulator-can contribute to the development of an aggressive cell phenotype. Owing to their ability to tether different molecules into functional complexes, scaffold proteins have a key role in the regulation of different signaling pathways in tumorigenesis...
March 29, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29590629/enhancer-activation-by-pharmacologic-displacement-of-lsd1-from-gfi1-induces-differentiation-in-acute-myeloid-leukemia
#5
Alba Maiques-Diaz, Gary J Spencer, James T Lynch, Filippo Ciceri, Emma L Williams, Fabio M R Amaral, Daniel H Wiseman, William J Harris, Yaoyong Li, Sudhakar Sahoo, James R Hitchin, Daniel P Mould, Emma E Fairweather, Bohdan Waszkowycz, Allan M Jordan, Duncan L Smith, Tim C P Somervaille
Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1's histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein...
March 27, 2018: Cell Reports
https://www.readbyqxmd.com/read/29581250/lsd1-activates-a-lethal-prostate-cancer-gene-network-independently-of-its-demethylase-function
#6
Archana Sehrawat, Lina Gao, Yuliang Wang, Armand Bankhead, Shannon K McWeeney, Carly J King, Jacob Schwartzman, Joshua Urrutia, William H Bisson, Daniel J Coleman, Sunil K Joshi, Dae-Hwan Kim, David A Sampson, Sheila Weinmann, Bhaskar V S Kallakury, Deborah L Berry, Reina Haque, Stephen K Van Den Eeden, Sunil Sharma, Jared Bearss, Tomasz M Beer, George V Thomas, Laura M Heiser, Joshi J Alumkal
Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR...
May 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29542357/treating-donor-cells-with-2-pcpa-corrects-aberrant-histone-h3k4-dimethylation-and-improves-cloned-goat-embryo-development
#7
Tingchao Mao, Chengquan Han, Ruizhi Deng, Biao Wei, Peng Meng, Yan Luo, Yong Zhang
Epigenetic modifications extensively occur in mammalian embryonic development and cell differentiation process. They play an essential role in the reprogramming of nuclei during somatic cell nuclear transfer (SCNT) and subsequent in vitro embryonic development. Recently, SCNT embryos have been verified to contain a subnormal level of histone H3K4 dimethylation (H3K4me2) in contrast to in vitro fertilized embryos. This finding suggested that increasing H3K4me2 levels may ameliorate the aberrant development of cloned embryos...
June 2018: Systems Biology in Reproductive Medicine
https://www.readbyqxmd.com/read/29534805/bioactivity-guided-cut-countercurrent-chromatography-for-isolation-of-lysine-specific-demethylase-1-inhibitors-from-scutellaria-baicalensis-georgi
#8
Chao Han, Shanshan Wang, Zhongrui Li, Chen Chen, Jiqin Hou, Dingqiao Xu, Ruizhi Wang, Yaolan Lin, Jianguang Luo, Lingyi Kong
Countercurrent chromatography (CCC) has gradually become a widely used method for preparative separation of bioactive natural molecules. These molecules generally contain distinct scaffolds and characteristics that cannot be readily isolated from plants. While one-dimensional CCC is typically used for the initial purification with insufficiently resolved peaks after locating bioactive components, two-dimensional (2D) or multi-dimensional CCC strategies are employed to improve the resolution of peaks. However, these methods usually present certain disadvantages, such as complicated procedures and increased time consumption, experimental costs, and equipment requirements...
August 3, 2018: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29533778/ory-1001-overcoming-the-differentiation-block-in-aml
#9
Prithviraj Bose, Marina Y Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001-an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)-in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.
March 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29524666/design-synthesis-and-biological-activity-of-4-4-benzyloxy-phenoxypiperidines-as-selective-and-reversible-lsd1-inhibitors
#10
Jiayue Xi, Siyuan Xu, Lulu Zhang, Xueyuan Bi, Yanshen Ren, Yu-Chih Liu, Yueqing Gu, Yungen Xu, Fei Lan, Xiaoming Zha
Lysine specific demethylase 1 (LSD1) plays a vital role in epigenetic regulation of gene activation and repression in several human cancers and is recognized as a promising antitumor therapeutic target. In this paper, a series of 4-(4-benzyloxy)phenoxypiperidines were synthesized and evaluated. Among the tested compounds, compound 10d exhibited the potent and reversible inhibitory activity against LSD1 in vitro (IC50  = 4 μM). Molecular docking was conducted to predict its binding mode. Furthermore, 10d displayed it could inhibit migration of HCT-116 colon cancer cells and A549 lung cancer cells...
February 16, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29496367/novel-polyamine-based-histone-deacetylases-lysine-demethylase-1-dual-binding-inhibitors
#11
Andrea Milelli, Chiara Marchetti, Eleonora Turrini, Elena Catanzaro, Roberta Mazzone, Daniela Tomaselli, Carmela Fimognari, Vincenzo Tumiatti, Anna Minarini
Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine...
April 1, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29464084/lysine-specific-demethylase-1-inhibitors-prevent-teratoma-development-from-human-induced-pluripotent-stem-cells
#12
Naoki Osada, Jiro Kikuchi, Takashi Umehara, Shin Sato, Masashi Urabe, Tomoyuki Abe, Nakanobu Hayashi, Masahiko Sugitani, Yutaka Hanazono, Yusuke Furukawa
Human induced pluripotent stem cells (hiPSCs) are creating great expectations for regenerative medicine. However, safety strategies must be put in place to guard against teratoma formation after transplantation of hiPSC-derived cells into patients. Recent studies indicate that epigenetic regulators act at the initial step of tumorigenesis. Using gain-of-function and loss-of-function approaches, we show here that the expression and function of lysine-specific demethylase 1 (LSD1) are tightly regulated in hiPSCs, and their deregulation underlies the development of teratomas...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29459279/cyclic-peptide-inhibitors-of-lysine-specific-demethylase-1-with-improved-potency-identified-by-alanine-scanning-mutagenesis
#13
Isuru R Kumarasinghe, Patrick M Woster
Lysine-specific demethylase 1 (LSD1) is a chromatin-remodeling enzyme that plays an important role in cancer. Over-expression of LSD1 decreases methylation at histone 3 lysine 4, and aberrantly silences tumor suppressor genes. Inhibitors of LSD1 have been designed as chemical probes and potential antitumor agents. We recently reported the cyclic peptide 9, which potently and reversibly inhibits LSD1 (IC50 2.1 μM; Ki 385 nM). Systematic alanine mutagenesis of 9 revealed residues that are critical for LSD1 inhibition, and these mutated peptides were evaluated as LSD1 inhibitors...
March 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29453291/lsd1-inhibition-exerts-its-antileukemic-effect-by-recommissioning-pu-1-and-c-ebp%C3%AE-dependent-enhancers-in-aml
#14
Monica Cusan, Sheng F Cai, Helai P Mohammad, Andrei Krivtsov, Alan Chramiec, Evangelia Loizou, Matthew D Witkin, Kimberly N Smitheman, Daniel G Tenen, Min Ye, Britta Will, Ulrich Steidl, Ryan G Kruger, Ross L Levine, Hugh Y Rienhoff, Richard P Koche, Scott A Armstrong
Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine-specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML...
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29439916/new-histone-demethylase-lsd1-inhibitor-selectively-targets-teratocarcinoma-and-embryonic-carcinoma-cells
#15
Nam Hoang, Xuan Zhang, Chunxiao Zhang, Van Vo, Feng Leng, Lovely Saxena, Feng Yin, Fei Lu, Guangrong Zheng, Pradip Bhowmik, Hui Zhang
LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4...
May 1, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29438700/targeting-the-senescence-overriding-cooperative-activity-of-structurally-unrelated-h3k9-demethylases-in-melanoma
#16
Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark R Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A Mallette, Leonard I Zon, Sheri L Holmen, Daniel S Peeper, Yardena Samuels, Clemens A Schmitt, Soyoung Lee
Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29370269/the-histone-demethylase-lsd1-regulates-inner-ear-progenitor-differentiation-through-interactions-with-pax2-and-the-nurd-repressor-complex
#17
Dharmeshkumar Patel, Atsushi Shimomura, Sreeparna Majumdar, Matthew C Holley, Eri Hashino
The histone demethylase LSD1 plays a pivotal role in cellular differentiation, particularly in silencing lineage-specific genes. However, little is known about how LSD1 regulates neurosensory differentiation in the inner ear. Here we show that LSD1 interacts directly with the transcription factor Pax2 to form the NuRD co-repressor complex at the Pax2 target gene loci in a mouse otic neuronal progenitor cell line (VOT-N33). VOT-N33 cells expressing a Pax2-response element reporter were GFP-negative when untreated, but became GFP positive after forced differentiation or treatment with a potent LSD inhibitor...
2018: PloS One
https://www.readbyqxmd.com/read/29343972/targeting-histone-methyltransferase-and-demethylase-in-acute-myeloid-leukemia-therapy
#18
REVIEW
Germana Castelli, Elvira Pelosi, Ugo Testa
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29331452/design-synthesis-and-evaluation-of-%C3%AE-turn-mimetics-as-lsd1-selective-inhibitors
#19
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity...
February 1, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29325932/riboflavin-attenuates-myocardial-injury-via-lsd1-mediated-crosstalk-between-phospholipid-metabolism-and-histone-methylation-in-mice-with-experimental-myocardial-infarction
#20
Peng Wang, Fan Fan, Xiao Li, Xiaolei Sun, Leilei Ma, Jian Wu, Cheng Shen, Hong Zhu, Zhen Dong, Cong Wang, Shuqi Zhang, Xiaona Zhao, Xin Ma, Yunzeng Zou, Kai Hu, Aijun Sun, Junbo Ge
The underlying mechanisms responsible for the cardioprotective effects of riboflavin remain elusive. Current study tested the hypothesis that riboflavin protects injured myocardium via epigenetic modification of LSD1. Here we showed that myocardial injury was attenuated and cardiac function was improved in riboflavin-treated mice with experimental myocardial infarction (MI), while these protective effects of riboflavin could be partly blocked by cotreatment with LSD1 inhibitor. Riboflavin also reduced apoptosis in hypoxic (1% oxygen) H9C2 cell lines...
February 2018: Journal of Molecular and Cellular Cardiology
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