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LSD1 inhibitor

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https://www.readbyqxmd.com/read/28722477/advances-toward-lsd1-inhibitors-for-cancer-therapy
#1
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
#2
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
#3
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-lds1-interactions-with-snag-domain-proteins-insm1-and-gfi1b
#4
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 anti-proliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here we describe the anti-cancer 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...
June 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/28617441/concomitant-epigenetic-targeting-of-lsd1-and-hdac-synergistically-induces-mitochondrial-apoptosis-in-rhabdomyosarcoma-cells
#5
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
#6
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
https://www.readbyqxmd.com/read/28571892/lpe-1-an-orally-active-pyrimidine-derivative-inhibits-growth-and-mobility-of-human-esophageal-cancers-by-targeting-lsd1
#7
Bo Wang, Bing Zhao, Lu-Ping Pang, Yuan-Di Zhao, Qian Guo, Jun-Wei Wang, Yi-Chao Zheng, Xin-Hui Zhang, Ying Liu, Guang-Yao Liu, Wen-Ge Guo, Chao Wang, Zhong-Hua Li, Xue-Jing Mao, Bin Yu, Li-Ying Ma, Hong-Min Liu
Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0...
May 30, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28545974/development-of-5-hydroxypyrazole-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#8
Daniel P Mould, Ulf Bremberg, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Helen F Small, Tim C P Somervaille, Donald Ogilvie
A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86...
May 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28486922/an-overview-on-screening-methods-for-lysine-specific-demethylase-1-lsd1-inhibitors
#9
Yi-Chao Zheng, Jiao Chang, Ting Zhang, Feng-Zhi Suo, Xiao-Bing Chen, Ying Liu, Bing Zhao, Bin Yu, Hong-Min Liu
BACKGROUND: In the past few years, lots of attention has been given to the identification and characterization of selective and potent inhibitors of the first identified histone demethylase LSD1, which may erase mono- and di-methylated histone 3 lysine 4 and 9. As the aberrant overexpression of LSD1 is involved in various pathological processes, especially cancer, obtaining selective and potent LSD1 inhibitors has emerged as a crucial issue in medicinal chemistry research. METHOD: Until now, several LSD1 inhibitor screening models have been established, including enzyme coupled assay, LC-MS based assay, FRET based assay...
May 8, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28460360/design-synthesis-and-biological-activity-of-3-oxoamino-benzenesulfonamides-as-selective-and-reversible-lsd1-inhibitors
#10
Jiayue Xi, Siyuan Xu, Liming Wu, Tianfang Ma, Rongfeng Liu, Yu-Chih Liu, Dawei Deng, Yueqing Gu, Jinpei Zhou, Fei Lan, Xiaoming Zha
Lysine specific demethylase 1 (LSD1) is a flavin-dependent amine oxidase that selectively removes one or two methyl groups from H3 at Lys4 and is recognized as a promising therapeutic target for cancer and other diseases. Here, a series of 3-oxoamino-benzenesulfonamides were synthesized and evaluated for their inhibitory activity against LSD1. Compounds 7b and 7h showed the most potent inhibition with the IC50 values of 9.5 and 6.9μM, respectively. Furthermore, the LSD1 inhibition of 7b and 7h were reversible and selective...
June 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28435523/discovery-of-1-2-3-triazolo-4-5-d-pyrimidine-derivatives-as-novel-lsd1-inhibitors
#11
Zhong-Hua Li, Xue-Qi Liu, Peng-Fei Geng, Feng-Zhi Suo, Jin-Lian Ma, Bin Yu, Tao-Qian Zhao, Zhao-Qing Zhou, Chen-Xi Huang, Yi-Chao Zheng, Hong-Min Liu
Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure-activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound 27 as potent LSD1 inhibitor (IC50 = 0...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28416745/stable-h3-peptide-was-delivered-by-gold-nanorods-to-inhibit-lsd1-activation-and-induce-human-mesenchymal-stem-cells-differentiation
#12
Xin Meng, Jianping Li, Minjuan Zheng, Lei Zuo, Chao Sun, Yongsheng Zhu, Ling Fang, Liwen Liu, Xiaodong Zhou
Recently, lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, regulates post-translational modifications and has great promise as new targets for cancer and other diseases. Moreover, the ability of LSD1 to induce the differentiation of stem cells has attracted great attention in biological fields. In this study, we designed LSD1 peptide inhibitor based on its substrate H3 peptide. Through introducing a disulfide bond to stabilize the native peptide into alpha helical structure, we get a peptide with higher cell permeability and stability compared to its parent form...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404874/identification-of-jl1037-as-a-novel-specific-reversible-lysine-specific-demethylase-1-inhibitor-that-induce-apoptosis-and-autophagy-of-aml-cells
#13
Shuang Liu, Wenting Lu, Shouyun Li, Saisai Li, Jia Liu, Yuanyuan Xing, Shuzu Zhang, Joe Zhongxiang Zhou, Haiyan Xing, Yingxi Xu, Qing Rao, Chengjun Deng, Min Wang, Jianxiang Wang
Lysine-specific demethylase 1 (LSD1) has been recognized as a potential therapeutic target for acute myeloid leukemia (AML). Herein, we identified a novel LSD1 inhibitor, JL1037, via Computer Aided Drug Design technology. JL1037 is a potent, selective and reversible LSD1 inhibitor with IC50s of 0.1 μM and >1.5 μM for LSD1 and monoamine oxidases A/B (MAO-A/B), respectively. Treatment of THP-1 and Kasumi-1 cell lines with JL1037 resulted in dose dependent accumulation of H3K4me1 and H3K4me2, the major substrates of LSD1, as well as inhibition of cell proliferation, blockade of cell cycle and induction of apoptosis...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28390942/fluorinated-tranylcypromine-analogues-as-inhibitors-of-lysine-specific-demethylase-1-lsd1-kdm1a
#14
Maria Teresa Borrello, Benjamin Schinor, Katharina Bartels, Hanae Benelkebir, Sara Pereira, Wafa T Al-Jamal, Leon Douglas, Patrick J Duriez, Graham Packham, Günter Haufe, A Ganesan
We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28377178/targeting-kdm1a-attenuates-wnt-%C3%AE-catenin-signaling-pathway-to-eliminate-sorafenib-resistant-stem-like-cells-in-hepatocellular-carcinoma
#15
Mengxi Huang, Cheng Chen, Jian Geng, Dong Han, Tao Wang, Tao Xie, Liya Wang, Ye Wang, Chunhua Wang, Zengjie Lei, Xiaoyuan Chu
Use of the tyrosine kinase inhibitor sorafenib in patients with advanced hepatocellular carcinoma (HCC) is often hindered by the development of resistance, which has been recently shown to be associated with the emergence of a cancer stem cell (CSC) subpopulation. However, it remains largely unknown whether epigenetic mechanisms, especially histone posttranslational modifications, are causally linked to the maintenance of stem-like properties in sorafenib-resistant HCC. In this study, we report that the activity of lysine-specific histone demethylase 1A (KDM1A or LSD1) is required for the emergence of cancer stem cells following prolonged sorafenib treatment...
July 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28336409/development-and-crystallographic-evaluation-of-histone-h3-peptide-with-n-terminal-serine-substitution-as-a-potent-inhibitor-of-lysine-specific-demethylase-1
#16
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
March 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28322226/highly-effective-combination-of-lsd1-kdm1a-antagonist-and-pan-histone-deacetylase-inhibitor-against-human-aml-cells
#17
W Fiskus, S Sharma, B Shah, B P Portier, S G T Devaraj, K Liu, S P Iyer, D Bearss, K N Bhalla
No abstract text is available yet for this article.
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28238805/pharmacological-inhibition-of-lsd1-and-mtor-reduces-mitochondrial-retention-and-associated-ros-levels-in-the-red-blood-cells-of-sickle-cell-disease
#18
Ramasamy Jagadeeswaran, Benjamin A Vazquez, Muthusamy Thiruppathi, Balaji B Ganesh, Vinzon Ibanez, Shuaiying Cui, James D Engel, Alan M Diamond, Robert E Molokie, Joseph DeSimone, Donald Lavelle, Angela Rivers
Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs), which accelerates their hemolysis...
February 24, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28219005/a-rhodium-iii-based-inhibitor-of-lysine-specific-histone-demethylase-1-as-an-epigenetic-modulator-in-prostate-cancer-cells
#19
Chao Yang, Wanhe Wang, Jia-Xin Liang, Guodong Li, Kasipandi Vellaisamy, Chun-Yuen Wong, Dik-Lung Ma, Chung-Hang Leung
We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells and enhanced the amplification of p21, FOXA2, and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7, and MAO activities, and also showed antiproliferative activity toward human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.
March 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#20
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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