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LSD1 inhibitor

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https://www.readbyqxmd.com/read/29075615/pharmacologic-targeting-of-chromatin-modulators-as-therapeutics-of-acute-myeloid-leukemia
#1
REVIEW
Rui Lu, Gang Greg Wang
Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29037950/discovery-of-tranylcypromine-analogs-with-an-acylhydrazone-substituent-as-lsd1-inactivators-design-synthesis-and-their-biological-evaluation
#2
Kai Sun, Jia-Di Peng, Feng-Zhi Suo, Ting Zhang, Yun-Dong Fu, Yi-Chao Zheng, Hong-Min Liu
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC50 = 91.83 nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29031059/tying-up-tranylcypromine-novel-selective-histone-lysine-specific-demethylase-1-lsd1-inhibitors
#3
Yue-Yang Ji, Sen-Dong Lin, Yu-Jie Wang, Ming-Bo Su, Wei Zhang, Hendra Gunosewoyo, Fan Yang, Jia Li, Jie Tang, Yu-Bo Zhou, Li-Fang Yu
Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28991226/lsd1-promotes-s-phase-entry-and-tumorigenesis-via-chromatin-co-occupation-with-e2f1-and-selective-h3k9-demethylation
#4
Y He, Y Zhao, L Wang, L R Bohrer, Y Pan, L Wang, H Huang
Histone H3 lysine-9 (H3K9) methylation is essential for retinoblastoma protein (RB)-mediated heterochromatin formation, epigenetic silencing of S-phase genes and permanent cell cycle arrest or cellular senescence. Besides as an H3K4 demethylase, lysine-specific demethylase-1 (LSD1) has been shown to promote H3K9 demethylation. However, it is unexplored whether LSD1 has a causal role in regulating cell cycle entry and senescence. Here we demonstrate that genetic depletion or pharmacological inhibition of LSD1 triggers G1 arrest and cellular senescence...
October 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28987602/design-and-synthesis-of-tranylcypromine-derivatives-as-novel-lsd1-hdacs-dual-inhibitors-for-cancer-treatment
#5
Ying-Chao Duan, Yong-Cheng Ma, Wen-Ping Qin, Li-Na Ding, Yi-Chao Zheng, Ying-Li Zhu, Xiao-Yu Zhai, Jing Yang, Chao-Ya Ma, Yuan-Yuan Guan
Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28955993/lsd1-kdm1-isoform-lsd1-8a-contributes-to-neural-differentiation-in-small-cell-lung-cancer
#6
Takanobu Jotatsu, Shigehiro Yagishita, Ken Tajima, Fumiyuki Takahashi, Kaoru Mogushi, Moulid Hidayat, Aditya Wirawan, Ryo Ko, Ryota Kanemaru, Naoko Shimada, Keiko Mitani, Tsuyoshi Saito, Kazuya Takamochi, Kenji Suzuki, Shinji Kohsaka, Shinya Kojima, Hiroshi Mukae, Kazuhiro Yatera, Kazuhisa Takahashi
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding...
March 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28927796/development-and-evaluation-of-4-pyrrolidin-3-yl-benzonitrile-derivatives-as-inhibitors-of-lysine-specific-demethylase-1
#7
Daniel P Mould, Ulf Bremberg, Allan M Jordan, Matthis Geitmann, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Donald J Ogilvie
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28892629/development-of-4-cyanophenyl-glycine-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#8
Daniel P Mould, Cristina Alli, Ulf Bremberg, Sharon Cartic, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Fabrice Turlais, Donald Ogilvie
Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1)...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892104/synergistic-anti-aml-effects-of-the-lsd1-inhibitor-t-3775440-and-the-nedd8-activating-enzyme-inhibitor-pevonedistat-via-transdifferentiation-and-dna-rereplication
#9
Y Ishikawa, K Nakayama, M Morimoto, A Mizutani, A Nakayama, K Toyoshima, A Hayashi, S Takagi, R Dairiki, H Miyashita, S Matsumoto, K Gamo, T Nomura, K Nakamura
Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation...
September 11, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28878246/loss-of-nr2e3-represses-ahr-by-lsd1-reprogramming-is-associated-with-poor-prognosis-in-liver-cancer
#10
Tilak Khanal, Kwangmin Choi, Yuet-Kin Leung, Jiang Wang, Dasom Kim, Vinothini Janakiram, Sung-Gook Cho, Alvaro Puga, Shuk-Mei Ho, Kyounghyun Kim
The aryl hydrocarbon receptor (AHR) plays crucial roles in inflammation, metabolic disorder, and cancer. However, the molecular mechanisms regulating AHR expression remain unknown. Here, we found that an orphan nuclear NR2E3 maintains AHR expression, and forms an active transcriptional complex with transcription factor Sp1 and coactivator GRIP1 in MCF-7 human breast and HepG2 liver cancer cell lines. NR2E3 loss promotes the recruitment of LSD1, a histone demethylase of histone 3 lysine 4 di-methylation (H3K4me2), to the AHR gene promoter region, resulting in repression of AHR expression...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28843610/role-of-the-dna-repair-glycosylase-ogg1-in-the-activation-of-murine-splenocytes
#11
Marco Seifermann, Alexander Ulges, Tobias Bopp, Svetlana Melcea, Andrea Schäfer, Sugako Oka, Yusaku Nakabeppu, Arne Klungland, Christof Niehrs, Bernd Epe
OGG1 (8-oxoguanine-DNA glycosylase) is the major DNA repair glycosylase removing the premutagenic DNA base modification 8-oxo-7,8-dihydroguanine (8-oxoG) from the genome of mammalian cells. In addition, there is accumulating evidence that OGG1 and its substrate 8-oxoG might function in the regulation of certain genes, which could account for an attenuated immune response observed in Ogg1(-/-) mice in several settings. Indications for at least two different mechanisms have been obtained. Thus, OGG1 could either act as an ancillary transcription factor cooperating with the lysine-specific demethylase LSD1 or as an activator of small GTPases...
October 2017: DNA Repair
https://www.readbyqxmd.com/read/28800922/inhibition-of-h3k4-demethylation-induces-autophagy-in-cancer-cell-lines
#12
Zhen Wang, Qiao-Yun Long, Lin Chen, Jia-Dong Fan, Zhao-Ning Wang, Lian-Yun Li, Min Wu, Xuefeng Chen
Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28783174/lysine-specific-demethylase-lsd1-regulates-autophagy-in-neuroblastoma-through-sesn2-dependent-pathway
#13
S Ambrosio, C D Saccà, S Amente, S Paladino, L Lania, B Majello
Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#14
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722477/advances-toward-lsd1-inhibitors-for-cancer-therapy
#15
Xiaoli Fu, Peng Zhang, Bin Yu
LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28722470/novel-potent-inhibitors-of-the-histone-demethylase-kdm1a-lsd1-orally-active-in-a-murine-promyelocitic-leukemia-model
#16
Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello
BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28699367/a-comprehensive-review-of-lysine-specific-demethylase-1-and-its-roles-in-cancer
#17
Amir Hosseini, Saverio Minucci
Histone methylation plays a key role in the regulation of chromatin structure, and its dynamics regulates important cellular processes. The investigation of the role of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Lysine-specific demethylase 1(LSD1, also known as KDM1A) is the first discovered histone lysine demethylase, with the ability to demethylase H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner...
July 12, 2017: Epigenomics
https://www.readbyqxmd.com/read/28667074/lsd1-inhibitor-t-3775440-inhibits-sclc-cell-proliferation-by-disrupting-lsd1-interactions-with-snag-domain-proteins-insm1-and-gfi1b
#18
Shinji Takagi, Yoshinori Ishikawa, Akio Mizutani, Shinji Iwasaki, Satoru Matsumoto, Yusuke Kamada, Toshiyuki Nomura, Kazuhide Nakamura
T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1 INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1...
September 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28617441/concomitant-epigenetic-targeting-of-lsd1-and-hdac-synergistically-induces-mitochondrial-apoptosis-in-rhabdomyosarcoma-cells
#19
Tinka Haydn, Eric Metzger, Roland Schuele, Simone Fulda
The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28610981/3d-qsar-comfa-comsia-molecular-docking-and-molecular-dynamics-simulations-study-of-6-aryl-5-cyano-pyrimidine-derivatives-to-explore-the-structure-requirements-of-lsd1-inhibitors
#20
Lina Ding, Zhi-Zheng Wang, Xu-Dong Sun, Jing Yang, Chao-Ya Ma, Wen Li, Hong-Min Liu
Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
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