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https://www.readbyqxmd.com/read/27926736/structure-of-cc-chemokine-receptor-2-with-orthosteric-and-allosteric-antagonists
#1
Yi Zheng, Ling Qin, Natalia V Ortiz Zacarías, Henk de Vries, Gye Won Han, Martin Gustavsson, Marta Dabros, Chunxia Zhao, Robert J Cherney, Percy Carter, Dean Stamos, Ruben Abagyan, Vadim Cherezov, Raymond C Stevens, Adriaan P IJzerman, Laura H Heitman, Andrew Tebben, Irina Kufareva, Tracy M Handel
CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer...
December 7, 2016: Nature
https://www.readbyqxmd.com/read/27926729/intracellular-allosteric-antagonism-of-the-ccr9-receptor
#2
Christine Oswald, Mathieu Rappas, James Kean, Andrew S Doré, James C Errey, Kirstie Bennett, Francesca Deflorian, John A Christopher, Ali Jazayeri, Jonathan S Mason, Miles Congreve, Robert M Cooke, Fiona H Marshall
Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases. Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization...
December 7, 2016: Nature
https://www.readbyqxmd.com/read/27926382/prediction-of-anti-cancer-drug-response-by-kernelized-multi-task-learning
#3
Mehmet Tan
MOTIVATION: Chemotherapy or targeted therapy are two of the main treatment options for many types of cancer. Due to the heterogeneous nature of cancer, the success of the therapeutic agents differs among patients. In this sense, determination of chemotherapeutic response of the malign cells is essential for establishing a personalized treatment protocol and designing new drugs. With the recent technological advances in producing large amounts of pharmacogenomic data, in silico methods have become important tools to achieve this aim...
October 2016: Artificial Intelligence in Medicine
https://www.readbyqxmd.com/read/27925398/cell-based-biohybrid-drug-delivery-systems-the-best-of-the-synthetic-and-natural-worlds
#4
Samagya Banskota, Parisa Yousefpour, Ashutosh Chilkoti
The goal of drug delivery is to deliver therapeutics to the site of disease while reducing unwanted side effects. In recent years, a diverse variety of synthetic nano and microparticles have been developed as drug delivery systems. The success of these systems for drug delivery lies in their ability to overcome biological barriers such as the blood-brain barrier, to evade immune clearance and avoid nonspecific biodistribution. This Review provides an overview of recent advances in the design of biohybrid drug delivery systems, which combine cells with synthetic systems to overcome some of these biological hurdles...
December 7, 2016: Macromolecular Bioscience
https://www.readbyqxmd.com/read/27924754/relevance-of-randomised-controlled-trials-in-oncology
#5
REVIEW
Ian F Tannock, Eitan Amir, Christopher M Booth, Saroj Niraula, Alberto Ocana, Bostjan Seruga, Arnoud J Templeton, Francisco Vera-Badillo
Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27924733/design-and-synthesis-of-1-4-dihydropyridine-derivatives-as-anti-cancer-agent
#6
Denish Viradiya, Sheefa Mirza, Faraz Shaikh, Rajesh Kakadiya, Anand Rathod, Nayan Jain, Rakesh Rawal, Anamik Shah
A series of 1,4-dihydropyridine based compounds bearing benzylpyridinium moiety have been designed and evaluated for in vitro anticancer activity against glioblastoma U87MG, lung cancer A549 and colorectal adenocarcinoma Caco-2 cell lines using the MTT assay. Among these compounds, 7b, 7d, 7e, and 7f exhibited potent anticancer activity against the cell lines tested. The cytotoxicity of the synthesized derivatives was compared to standard drugs (carboplatin, gemcitabine, and daunorubicin). Thus, synthesized 1,4-dihydropyridines can be considered as the encouraging molecules for further drug development as anticancer agents...
December 6, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27924487/antagonists-of-the-mirna-argonaute-2-protein-complex-anti-mir-agos
#7
Marco F Schmidt, Oliver Korb, Chris Abell
microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs' functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein's active site...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924480/design-of-multimodal-small-molecules-targeting-mirnas-biogenesis-synthesis-and-in-vitro-evaluation
#8
Duc D Vo, Maria Duca
microRNAs (miRNAs) are emerging as novel biological targets for medicinal chemists to develop chemical tools for intracellular regulation. In this context, the discovery of small-molecule drugs targeting specific miRNAs and modulating their production or function represents a very promising approach that could be further developed for targeted therapy in miRNA-related pathologies. Here, we describe the design of multimodal small molecules as RNA ligands targeting DICER-mediated miRNA maturation. The synthesis and the biochemical evaluation as ligands of stem-loop-structured precursor microRNAs (pre-miRNAs) are reported...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27924312/protein-ligand-interaction-detection-with-a-novel-method-of-transient-induced-molecular-electronic-spectroscopy-times-experimental-and-theoretical-studies
#9
Tiantian Zhang, Tao Wei, Yuanyuan Han, Heng Ma, Mohammadreza Samieegohar, Ping-Wei Chen, Ian Lian, Yu-Hwa Lo
Protein-ligand interaction detection without disturbances (e.g., surface immobilization, fluorescent labeling, and crystallization) presents a key question in protein chemistry and drug discovery. The emergent technology of transient induced molecular electronic spectroscopy (TIMES), which incorporates a unique design of microfluidic platform and integrated sensing electrodes, is designed to operate in a label-free and immobilization-free manner to provide crucial information for protein-ligand interactions in relevant physiological conditions...
November 23, 2016: ACS Central Science
https://www.readbyqxmd.com/read/27924160/multivalent-targeting-based-delivery-of-therapeutic-peptide-using-ap1-elp-carrier-for-effective-cancer-therapy
#10
Vijaya Sarangthem, Yunjae Kim, Thoudam Debraj Singh, Bo-Yeon Seo, Sun-Ha Cheon, Young-Jin Lee, Byung-Heon Lee, Rang-Woon Park
Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell-targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK...
2016: Theranostics
https://www.readbyqxmd.com/read/27924159/in-vitro-and-in-vivo-evaluation-of-89-zr-ds-8273a-as-a-theranostic-for-anti-death-receptor-5-therapy
#11
Ingrid J G Burvenich, Fook-Thean Lee, Nancy Guo, Hui K Gan, Angela Rigopoulos, Adam C Parslow, Graeme J O'Keefe, Sylvia J Gong, Henri Tochon-Danguy, Stacey E Rudd, Paul S Donnelly, Masakatsu Kotsuma, Toshiaki Ohtsuka, Giorgio Senaldi, Andrew M Scott
Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design. Methods: DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessed in vitro...
2016: Theranostics
https://www.readbyqxmd.com/read/27924157/biodegradable-nitrogen-doped-carbon-nanodots-for-non-invasive-photoacoustic-imaging-and-photothermal-therapy
#12
Changho Lee, Woosung Kwon, Songeun Beack, Donghyun Lee, Yoonsang Park, Hyemin Kim, Sei Kwang Hahn, Shi-Woo Rhee, Chulhong Kim
Multifunctional nanoparticles have been widely investigated for biomedical applications, such as imaging, therapy, and drug delivery. Especially, photoactive nanoparticles have received great attention as theranostic agents because of their heat-generating abilities after exposure to laser irradiation. However, photostability and safety issues have been the technical hurdles for further clinical applications. Here, we designed nitrogen (N)-doped carbon nanodots (N-CNDs) that have strong absorption in the near-infrared region, high photostability, and excellent biodegradability...
2016: Theranostics
https://www.readbyqxmd.com/read/27923840/osimertinib-for-the-treatment-of-metastatic-epidermal-growth-factor-t970m-positive-non-small-cell-lung-cancer
#13
Sean Khozin, Chana Weinstock, Gideon M Blumenthal, Joyce Cheng, Kun He, Luning Zhuang, Hong Zhao, Rosane Charlab Orbach, Ingrid Fan, Patricia Keegan, Richard Pazdur
On November 13, 2015, FDA granted accelerated approval to osimertinib (TAGRISSO™; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (AURA extension; n=201) and a fixed-dose, activity-estimating trial (AURA2; n=210)...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27923714/brief-report-acquired-braf-v600e-mutation-as-resistant-mechanism-after-treatment-with-osimertinib
#14
Chao-Chi Ho, Wei-Yu Liao, Chih-An Lin, Jin-Yuan Shih, Chong-Jen Yu, James Chih-Hsin Yang
INTRODUCTION: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a resistant mechanism in patients after osimertinib treatment. METHODS: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib...
December 3, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27923697/layer-by-layer-nanoparticle-platform-for-cancer-active-targeting
#15
Min Sung Suh, Jie Shen, Liisa T Kuhn, Diane J Burgess
Nanoparticles as drug delivery carriers have been investigated over the last few decades, particularly for cancer treatment. The rationale in developing such nanoparticles is to maximize drug efficacy while minimizing toxic side effects. This can be most effectively achieved through target specific drug delivery. A novel biocompatible nanoparticle platform prepared using the core-shell self-assembly technique is reported. The core consists of calcium phosphate which is biocompatible and pH-sensitive, and the shell is composed of biocompatible polymers (hyaluronic acid, CD44 targeting moiety; and chitosan, physical cross-linker)...
December 3, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27923588/autophagy-and-akt-creb-signalling-play-an-important-role-in-the-neuroprotective-effect-of-nimodipine-in-a-rat-model-of-vascular-dementia
#16
Ming Hu, Zhijuan Liu, Peiyuan Lv, Hebo Wang, Yifei Zhu, Qianqian Qi, Jing Xu
The Akt/CREB signalling pathway is involved in neuronal survival and protection. Autophagy is also likely to be involved in survival mechanisms. Nimodipine is an L-type calcium channel antagonist that reduces excessive calcium influx during pathological conditions (contributing to its neuroprotective properties). However, the potential role of nimodipine in autophagic and Akt/CREB signalling is not well understood. In addition, little is known about the relationship between autophagic and Akt/CREB signalling...
December 3, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27923535/multitarget-drug-design-strategy-against-alzheimer-s-disease-homoisoflavonoid-mannich-base-derivatives-serve-as-acetylcholinesterase-and-monoamine-oxidase-b-dual-inhibitors-with-multifunctional-properties
#17
Yan Li, Xiaoming Qiang, Li Luo, Xia Yang, Ganyuan Xiao, Yunxiaozhu Zheng, Zhongcheng Cao, Zhipei Sang, Fu Su, Yong Deng
A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50=2.49±0.08nM and 1.74±0.0581μM, respectively), good self- and Cu(2+)-induced Aβ1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability...
November 28, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27923491/experimental-design-for-determination-of-effects-of-superdisintegrant-combinations-on-liquisolid-system-properties
#18
Barbora Vraníková, Sylvie Pavloková, Jan Gajdziok
The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets...
December 3, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27923197/single-chain-fc-dimer-human-growth-hormone-fusion-protein-for-improved-drug-delivery
#19
Li Zhou, Hsuan-Yao Wang, Shanshan Tong, Curtis T Okamoto, Wei-Chiang Shen, Jennica L Zaro
Fc fusion protein technology has been successfully used to generate long-acting forms of several protein therapeutics. In this study, a novel Fc-based drug carrier, single chain Fc-dimer (sc(Fc)2), was designed to contain two Fc domains recombinantly linked via a flexible linker. Since the Fc dimeric structure is maintained through the flexible linker, the hinge region was omitted to further stabilize it against proteolysis and reduce FcγR-related effector functions. The resultant sc(Fc)2 candidate preserved the neonatal Fc receptor (FcRn) binding...
November 27, 2016: Biomaterials
https://www.readbyqxmd.com/read/27922917/adherence-to-oral-administration-of-endocrine-treatment-in-patients-with-breast-cancer-a-qualitative-study
#20
Laura Iacorossi, Francesca Gambalunga, Alessandra Fabi, Diana Giannarelli, Anna Marchetti, Michela Piredda, Maria Grazia De Marinis
BACKGROUND: Breast cancer is the most common cancer in women in the world, and it is also the leading cause of cancer deaths among women. Nevertheless, breast cancer survival has increased as a result of improvements in early diagnosis and therapy, for example, oral endocrine therapy. Despite the importance of adherence to endocrine therapy, its trend appears complex and multidimensional and therefore has many loopholes and missing information. OBJECTIVE: The study aims to explore the experiences of adherence to endocrine therapy in women with breast cancer and their perceptions of the challenges they face in adhering to their medication prescribed...
December 5, 2016: Cancer Nursing
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