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https://www.readbyqxmd.com/read/28526922/advances-in-systemic-therapy-for-metastatic-breast-cancer-future-perspectives
#1
REVIEW
S P Corona, N Sobhani, A Ianza, G Roviello, G Mustacchi, M Bortul, F Zanconati, D Generali
Breast cancer (BC) is the most common cancer in women worldwide. One in eight women will develop the disease in her lifetime. Notwithstanding the incredible progress made in this field, BC still represents the second most common cause of cancer-related death in women. Targeted drugs have revolutionised breast cancer treatment and improved the prognosis as well as the life expectancy of millions of women. However, the phenomenon of primary and secondary pharmacological resistance is becoming increasingly evident, limiting the efficacy of these agents and calling for a better in-depth knowledge and understanding of the biology as well as the biochemical crosstalk underlying the disease...
July 2017: Medical Oncology
https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#2
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526263/n-stearoyl-l-tyrosine-inhibits-the-cell-senescence-and-apoptosis-induced-by-h2o2-in-hek293-tau-cells-via-the-cb2-receptor
#3
Yue Hu, Kai-Yi Zhou, Ze-Jian Wang, Yang Lu, Ming Yin
Although considerable energy and money have been spent trying to inhibit Aβ production and its related metabolic enzyme activities, there are still no drug treatments available to cure even slow for Alzheimer's disease. Therefore, tau protein has been focused recently as the new target for the treatment of Alzheimer's disease. The transfected human embryonic kidney 293 (HEK 293) cells with or without Tau 411 plasmid were used to evaluate the effect of tau protein on cell viability. H2O2 was added to simulate microenvironment of oxidative stress (OS) during aging...
May 16, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28526132/old-and-novel-functions-of-caspase-2
#4
M A Miles, T Kitevska-Ilioski, C J Hawkins
Although caspase-2 is a highly conserved protease that has received a lot of research attention, consensus about its roles and the molecular mechanisms that underpin them has been elusive. Recent improvements to our understanding of the activities of caspase-2 have been facilitated by the development and refinement of techniques allowing identification of cellular processes instigated by this caspase. Following DNA damage, caspase-2 can be activated in a molecular complex called the "PIDDosome"; however, other stimuli provoke caspase-2-dependent activities that do not appear to involve this complex...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28526131/metabolic-alterations-at-the-crossroad-of-aging-and-oncogenesis
#5
L Raffaghello, V Longo
Aging represents the major risk factor for cancer. Cancer and aging are characterized by a similar dysregulated metabolism consisting in upregulation of glycolysis and downmodulation of oxidative phosphorylation. In this respect, metabolic interventions can be viewed as promising strategies to promote longevity and to prevent or delay age-related disorders including cancer. In this review, we discuss the most promising metabolic approaches including chronic calorie restriction, periodic fasting/fasting-mimicking diets, and pharmacological interventions mimicking calorie restriction...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28525838/design-synthesis-and-evaluation-of-azaacridine-derivatives-as-dual-target-egfr-and-src-kinase-inhibitors-for-antitumor-treatment
#6
Zhishan Cui, Shaopeng Chen, Yanwei Wang, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525371/arsenic-trioxide-and-angiotensin-ii-have-inhibitory-effects-on-herg-protein-expression-evidence-for-the-role-of-pml-sumoylation
#7
Yu Liu, Duo Li, Dan Nie, Shang-Kun Liu, Fang Qiu, Mei-Tong Liu, Yuan-Yuan Li, Jia-Xin Wang, Yan-Xin Liu, Chang-Jiang Dong, Di Wu, Wei Tian, Jia Yang, Wei Mu, Jia-Tong Li, Dan Zhao, Xiao-Feng Wang, Wen-Feng Chu, Bao-Feng Yang
The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525267/the-supernatant-from-hepatocyte-cultures-with-drugs-that-cause-idiosyncratic-liver-injury-activates-macrophage-inflammasomes
#8
Ryuji Kato, Jack Uetrecht
There is increasing evidence that most idiosyncratic drug-induced liver injury (IDILI) is immune mediated, and in most cases reactive metabolites appear to be responsible for induction of this immune response. Reactive metabolites can cause cell damage with the release of damage-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Presumably the reason that the liver is a common target of idiosyncratic drug reactions is because it is the major site of drug metabolism and reactive metabolite formation...
May 19, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28524785/development-of-genipin-crosslinked-fucoidan-chitosan-n-arginine-nanogels-for-preventing-helicobacter-infection
#9
Yu-Hsin Lin, Kun-Ying Lu, Ching-Li Tseng, Jui-Yu Wu, Chien-Ho Chen, Fwu-Long Mi
AIM: This study aims to validate the anti-Helicobacter pylori efficacy of amoxicillin-loaded nanoparticles and nanogels with pH-responsive and site-specific drug release properties against H. pylori infection. MATERIALS & METHODS: Genipin-crosslinked low molecular weight fucoidan/chitosan-N-arginine nanogels (FCSA) were prepared for targeted delivery of amoxicillin to the site of H. pylori infected AGS gastric epithelial cells. RESULTS: The negatively charged nanogels (n-FCSA) adhered to H...
May 19, 2017: Nanomedicine
https://www.readbyqxmd.com/read/28524783/quantitative-analysis-of-veterinary-drugs-in-bovine-muscle-and-milk-by-liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry
#10
Shizuka Saito-Shida, Takatoshi Sakai, Satoru Nemoto, Hiroshi Akiyama
A simple and reliable multiresidue method for quantitative determination of veterinary drugs in bovine muscle and milk using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) was developed. Critical MS parameters such as capillary voltage, cone voltage, collision energy, desolvation gas temperature, and extraction mass window were carefully optimised to obtain the best possible sensitivity. Analytical samples were prepared using extraction with acetonitrile and hexane in the presence of anhydrous sodium sulphate and acetic acid, followed by ODS cartridge clean-up...
May 19, 2017: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
https://www.readbyqxmd.com/read/28524659/synthesis-molecular-docking-molecular-dynamics-studies-and-biological-evaluation-of-4h-chromone-1-2-3-4-tetrahydropyrimidine-5-carboxylate-derivatives-as-potential-anti-leukemic-agents
#11
Zahra Dolatkhah, Shahrzad Javanshir, Ahmad Shahir Sadr, Jaber Hosseini, Soroush Sardari
Series of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate and urea or thiourea, using MCM-41-SO3H as an efficient Nano-catalysts, and evaluated for their anti-cancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP...
May 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28524624/pulmonary-arterial-hypertension-progress-in-understanding-the-disease-and-prioritizing-strategies-for-drug-development
#12
REVIEW
P Ghataorhe, C J Rhodes, L Harbaum, M Attard, J Wharton, M R Wilkins
Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease...
May 19, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28524069/helical-plant-viral-nanoparticles-bioinspired-synthesis-of-nanomaterials-and-nanostructures
#13
Kannan Badri Narayanan, Sung Soo Han
Viral nanotechnology is revolutionizing the biomimetic and bioinspired synthesis of novel nanomaterials. Bottom-up nanofabrication by self-assembly of individual molecular components of elongated viral nanoparticles (VNPs) and virus-like particles (VLPs) has resulted in the production of superior materials and structures in the nano(bio)technological fields. Viral capsids are attractive materials, because of their symmetry, monodispersity, and polyvalency. Helical VNPs/VLPs are unique prefabricated nanoscaffolds with large surface area to volume ratios and high aspect ratios, and enable the construction of exquisite supramolecular nanostructures...
May 19, 2017: Bioinspiration & Biomimetics
https://www.readbyqxmd.com/read/28523999/molecular-docking-studies-applied-to-a-dataset-of-cruzain-inhibitors
#14
Edeildo Ferreira da Silva-Júnior, Paulo Henrique Barcellos França, Frederico Fávaro Ribeiro, Francisco Jaime Bezerra Mendonça-Júnior, Luciana Scotti, Marcus Tullius Scotti, Thiago Mendonça de Aquino, João Xavier de Araújo-Júnior
BACKGROUND: Chagas' disease is one of the main causes of heart failure in developing countries. The disadvantages of current therapy include the undesirable side-effects, resistance, and therapeutic adhesion. The development of new efficient and safe drugs is, therefore, an issue of extreme importance. OBJECTIVES: In order to gain a better understanding of how the compounds interact with the target, computational methods are essential. METHOD: In this theoretical study, we report a docking protocol applied to a dataset of 173 cruzain inhibitors with IC50 values of less than 10 μM, belonging 16 different chemical classes...
May 18, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28523998/uncovering-drug-mechanism-of-action-by-proteome-wide-identification-of-drug-binding-proteins
#15
Tao Cui, Hai Hou, Yao Sun, Huaixing Cang, Xiangxi Wang
Small molecule drugs obtained from synthetic compounds or natural products show their therapeutic effects by specifically binding to one or a few target proteins and modulating their functions. In contrast, undesirable drug-protein interactions may provoke harmful side effects. Furthermore, drug-protein interactions also play roles in drug activation, transport, metabolism and regulation of drug resistance. Therefore, systematically identifying binding proteins of a drug molecule is critical for understanding the mechanism of action of the drug at molecular level...
May 18, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28523650/ubiquitin-specific-peptidase-5-mediates-histidine-rich-protein-hpn-induced-cell-apoptosis-in-hepatocellular-carcinoma-through-p14-p53-signaling
#16
Yi Liu, Wei-Mao Wang, Li-Yi Zou, Li Li, Lu Feng, Ming-Zhu Pan, Min-Yi Lv, Ying Cao, Hua Wang, Hsiang-Fu Kung, Jian-Xin Pang, Wei-Ming Fu, Jin-Fang Zhang
Hpn is a small histidine-rich cytoplasmic protein from Helicobacter pylori and has been recognized as a high-risk factor for several cancers including gastric cancer, colorectal cancer, and MALT lymphoma. However, the relationship between Hpn and cancers remains elusive. In this study, we discovered that Hpn protein effectively suppressed cell growth and induced apoptosis in hepatocellular carcinoma (HCC). A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics was performed to find the molecular targets of Hpn in HCC cells...
May 18, 2017: Proteomics
https://www.readbyqxmd.com/read/28523625/identification-of-a-novel-putative-inhibitor-of-the-plasmodium-falciparum-purine-nucleoside-phosphorylase-exploring-the-purine-salvage-pathway-to-design-new-antimalarial-drugs
#17
Luciano Porto Kagami, Gustavo Machado das Neves, Ricardo Pereira Rodrigues, Vinicius Barreto da Silva, Vera Lucia Eifler-Lima, Daniel Fábio Kawano
Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria...
May 18, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28523546/histone-modifications-in-major-depressive-disorder-and-related-rodent-models
#18
Jan M Deussing, Mira Jakovcevski
Major depressive disorder (MDD) is a multifactorial disease, weakly linked to multiple genetic risk factors. In contrast to that, environmental factors and "gene × environment" interaction between specific risk genes and environmental factors, such as severe or early stress exposure, have been strongly linked to MDD vulnerability. Stressors can act on the interface between an organism and the environment, the epigenome. The molecular foundation for the impact of stressors on the risk to develop MDD is based on the hormonal stress response itself: the glucocorticoid receptor (GR, encoded by NR3C1)...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28522847/a-molecular-basis-for-selective-antagonist-destabilization-of-dopamine-d3-receptor-quaternary-organization
#19
Sara Marsango, Gianluigi Caltabiano, Mireia Jiménez-Rosés, Mark J Millan, John D Pediani, Richard J Ward, Graeme Milligan
The dopamine D3 receptor (D3R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D3R quaternary structure to promote monomerization...
May 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28522584/cooperative-targets-of-combined-mtor-hdac-inhibition-promote-myc-degradation
#20
John K Simmons, Aleksandra M Michalowski, Benjamin J Gamache, Wendy DuBois, Jyoti Patel, Ke Zhang, Joy Gary, Shuling Zhang, Snehal Gaikwad, Daniel Connors, Nicholas Watson, Elena Leon, Jin-Qiu Chen, W Michael Kuehl, Maxwell P Lee, Adriana Zingone, Ola Landgren, Peter Ordentlich, Jing Huang, Beverly A Mock
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents.  In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents...
May 18, 2017: Molecular Cancer Therapeutics
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