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https://www.readbyqxmd.com/read/28342455/repair-of-oxidatively-induced-dna-damage-by-dna-glycosylases-mechanisms-of-action-substrate-specificities-and-excision-kinetics
#1
REVIEW
Miral Dizdaroglu, Erdem Coskun, Pawel Jaruga
Endogenous and exogenous reactive species cause oxidatively induced DNA damage in living organisms by a variety of mechanisms. As a result, a plethora of mutagenic and/or cytotoxic products are formed in cellular DNA. This type of DNA damage is repaired by base excision repair, although nucleotide excision repair also plays a limited role. DNA glycosylases remove modified DNA bases from DNA by hydrolyzing the glycosidic bond leaving behind an apurinic/apyrimidinic (AP) site. Some of them also possess an accompanying AP-lyase activity that cleaves the sugar-phosphate chain of DNA...
January 2017: Mutation Research
https://www.readbyqxmd.com/read/28340496/recent-developments-in-nanomedicine-for-melanoma-treatment
#2
REVIEW
Jian-Qin Tang, Xiao-Yang Hou, Chun-Sheng Yang, Ya-Xi Li, Yong Xin, Wen-Wen Guo, Zhi-Ping Wei, Yan-Qun Liu, Guan Jiang
Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy...
March 24, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28340378/current-fda-approved-treatments-for-non-small-cell-lung-cancer-and-potential-biomarkers-for-its-detection
#3
REVIEW
Karla A Ruiz-Ceja, Yolanda I Chirino
BACKGROUND: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action? AIM: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection...
March 21, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28336914/inhibition-of-serum-and-glucocorticoid-regulated-kinase-1-as-novel-therapy-for-cardiac-arrhythmia-disorders
#4
Vassilios J Bezzerides, Aifeng Zhang, Ling Xiao, Bridget Simonson, Santosh A Khedkar, Shiro Baba, Filomena Ottaviano, Stacey Lynch, Katherine Hessler, Alan C Rigby, David Milan, Saumya Das, Anthony Rosenzweig
Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28335719/enhanced-construction-of-gene-regulatory-networks-using-hub-gene-information
#5
Donghyeon Yu, Johan Lim, Xinlei Wang, Faming Liang, Guanghua Xiao
BACKGROUND: Gene regulatory networks reveal how genes work together to carry out their biological functions. Reconstructions of gene networks from gene expression data greatly facilitate our understanding of underlying biological mechanisms and provide new opportunities for biomarker and drug discoveries. In gene networks, a gene that has many interactions with other genes is called a hub gene, which usually plays an essential role in gene regulation and biological processes. In this study, we developed a method for reconstructing gene networks using a partial correlation-based approach that incorporates prior information about hub genes...
March 23, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28334643/dual-tail-approach-to-discovery-of-novel-carbonic-anhydrase-ix-inhibitors-by-simultaneously-matching-the-hydrophobic-and-hydrophilic-halves-of-the-active-site
#6
Zhuang Hou, Bin Lin, Yu Bao, Hai-Ning Yan, Miao Zhang, Xiao-Wei Chang, Xin-Xin Zhang, Zi-Jie Wang, Gao-Fei Wei, Mao-Sheng Cheng, Yang Liu, Chun Guo
Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site. In comparison with sulfanilamide which is largely devoid of the hydrophilic and hydrophobic interactions with the two halves of the active site, the compounds so designed and synthesized in this study showed 1000-fold improvement in binding affinity...
March 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28333459/6-oh-phenanthroquinolizidine-alkaloid-and-its-derivatives-exert-potent-anticancer-activity-by-delaying-s-phase-progression
#7
Yuxiu Liu, Lihua Qing, Chuisong Meng, Jiajie Shi, Yan Yang, Ziwen Wang, Guifang Han, Yi Wang, Jian Ding, Ling-Hua Meng, Qingmin Wang
To discover new phenanthroindolizidine and phenanthroquinolizidine alkaloids as potential anticancer drug candidates, non-natural 6-O-desmethylcryptopleurine (2) and its derivatives were prepared. Most of the new compounds exhibited potent antiproliferative activity against A549 and BEL-7402 cells, with the lowest IC50 being 3 nM. Optically pure 2-R was further evaluated against a panel of 30 cancer cell lines and found to inhibit the proliferation of all tested cell lines, including three multidrug-resistant cell lines, with an average IC50 value of 2...
March 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28331002/personalized-in-vitro-and-in-vivo-cancer-models-to-guide-precision-medicine
#8
Chantal Pauli, Benjamin D Hopkins, Davide Prandi, Reid Shaw, Tarcisio Fedrizzi, Andrea Sboner, Verena Sailer, Michael Augello, Loredana Puca, Rachele Rosati, Terra J McNary, Yelena Churakova, Cynthia Cheung, Joanna Triscott, David Pisapia, Rema Rao, Juan Miguel Mosquera, Brian Robinson, Bishoy M Faltas, Brooke E Emerling, Vijayakrishna K Gadi, Brady Bernard, Olivier Elemento, Himisha Beltran, Francesca Demichelis, Christopher J Kemp, Carla Grandori, Lewis C Cantley, Mark A Rubin
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial...
March 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28330821/beyond-precision-surgery-molecularly-motivated-precision-care-for-gastric-cancer
#9
REVIEW
Y Y Choi, J-H Cheong
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes...
March 1, 2017: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28330089/discovery-of-potential-alk-inhibitors-by-virtual-screening-approach
#10
Anish Kumar, V Shanthi, K Ramanathan
Crizotinib is an anticancer drug used for the treatment of non-small cell lung cancer. Evidences available suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene. It is therefore necessary to develop potent anti-cancer drugs for the treatment of crizotinib resistance non-small cell lung cancer types. In the present study, a novel class of lead molecule was identified using virtual screening, molecular docking and molecular dynamic approach...
June 2016: 3 Biotech
https://www.readbyqxmd.com/read/28328318/toward-discovery-of-novel-microtubule-targeting-agents-a-snap-tag-based-high-content-screening-assay-for-the-analysis-of-microtubule-dynamics-and-cell-cycle-progression
#11
Nina Berges, Katharina Arens, Verena Kreusch, Rainer Fischer, Stefano Di Fiore
Microtubule targeting agents (MTAs) are used for the treatment of cancer. Novel MTAs could provide additional and beneficial therapeutic options. To improve the sensitivity and throughput of standard immunofluorescence assays for the characterization of MTAs, we used SNAP-tag technology to produce recombinant tubulin monomers. To visualize microtubule filaments, A549 cells transfected with SNAP-tubulin were stained with a membrane-permeable, SNAP-reactive dye. The treatment of SNAP-tubulin cells with stabilizing MTAs such as paclitaxel resulted in the formation of coarsely structured microtubule filaments, whereas depolymerizing MTAs such as nocodazole resulted in diffuse staining patterns in which the tubulin filaments were no longer distinguishable...
April 2017: SLAS Discov
https://www.readbyqxmd.com/read/28327740/molecular-dynamics-simulations-elucidate-conformational-selection-and-induced-fit-mechanisms-in-the-binding-of-pd-1-and-pd-l1
#12
Wenping Liu, Bing Huang, Yashu Kuang, Guangjian Liu
Blockage of the interactions between immunologic checkpoint protein PD-1 and its ligand PD-L1 showed efficacy for cancer treatment. X-ray structures have captured static conformational snapshots of PD-1 and revealed that the CC' loop adopts an open conformation in the apo-protein but turns into a closed form and interacts with PD-L1 in the complex. This structural heterogeneity brings difficulties for structure-based drug discovery targeting PD-1. To gain insights into the role of the CC' loop in molecular recognition, we have undertaken a comparative study between the open and closed conformations in apo-PD-1 and the PD-1/PD-L1 complex using molecular dynamics simulations...
March 22, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28325214/antibody-based-cancer-therapy-successful-agents-and-novel-approaches
#13
D Hendriks, G Choi, M de Bruyn, V R Wiersma, E Bremer
Since their discovery, antibodies have been viewed as ideal candidates or "magic bullets" for use in targeted therapy in the fields of cancer, autoimmunity, and chronic inflammatory disorders. A wave of antibody-dedicated research followed, which resulted in the clinical approval of a first generation of monoclonal antibodies for cancer therapy such as rituximab (1997) and cetuximab (2004), and infliximab (2002) for the treatment of autoimmune diseases. More recently, the development of antibodies that prevent checkpoint-mediated inhibition of T cell responses invigorated the field of cancer immunotherapy...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28324785/-ub006-a-new-fatty-acid-synthase-inhibitor-and-cytotoxic-agent-without-anorexic-side-effects
#14
Kamil Makowski, Joan Francesc Mir, Paula Mera, Xavier Ariza, Guillermina Asins, Fausto G Hegardt, Laura Herrero, Jordi García, Dolors Serra
C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately...
March 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28323021/the-challenge-of-targeting-cancer-stem-cells-to-halt-metastasis
#15
REVIEW
Alice Agliano, Alfonso Calvo, Carol Box
Despite a continuing debate about the existence of cancer stem cells (CSCs), recent discoveries have provided further support for their existence and their roles in drug resistance, cancer recurrence and metastasis. CSC characteristics, such as self-renewal and tumour initiation, and supporting cellular processes, particularly the epithelial-to-mesenchymal transition, are attracting a great deal of attention from cancer researchers as they offer opportunities for discovering novel therapeutic targets for future drug development...
March 16, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28322271/mechanistic-and-structural-basis-of-bioengineered-bovine-cathelicidin-5-with-optimized-therapeutic-activity
#16
Bikash R Sahoo, Kenta Maruyama, Jyotheeswara R Edula, Takahiro Tougan, Yuxi Lin, Young-Ho Lee, Toshihiro Horii, Toshimichi Fujiwara
Peptide-drug discovery using host-defense peptides becomes promising against antibiotic-resistant pathogens and cancer cells. Here, we customized the therapeutic activity of bovine cathelicidin-5 targeting to bacteria, protozoa, and tumor cells. The membrane dependent conformational adaptability and plasticity of cathelicidin-5 is revealed by biophysical analysis and atomistic simulations over 200 μs in thymocytes, leukemia, and E. coli cell-membranes. Our understanding of energy-dependent cathelicidin-5 intrusion in heterogeneous membranes aided in designing novel loss/gain-of-function analogues...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28320616/high-content-screen-using-zebrafish-danio-rerio-embryos-identifies-a-novel-kinase-activator-and-inhibitor
#17
Werner J Geldenhuys, Sadie A Bergeron, Jackie E Mullins, Rowaa Aljammal, Briah L Gaasch, Wei-Chi Chen, June Yun, Lori A Hazlehurst
In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10μM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos...
February 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28318251/molecular-simulation-studies-on-the-binding-selectivity-of-type-i-inhibitors-in-the-complexes-with-ros1-versus-alk
#18
Yuanxin Tian, Yonghuan Yu, Yudong Shen, Hua Wan, Shan Chang, Tingting Zhang, Shanhe Wan, Jiajie Zhang
ROS1 and ALK are promising targets of anti-cancer drugs for non small cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, selective ROS1 inhibitor is relative rarely. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#19
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28316026/zebrafish-as-a-model-to-evaluate-peptide-related-cancer-therapies
#20
REVIEW
Austin Y Shull, Chien-An A Hu, Yong Teng
Peptide-derived drug discovery has experienced a remarkable resurgence in the past decade since the failure of small-molecule modulators to effectively access the large binding surfaces of intracellular protein-protein interactions as well as "undruggable" residues of certain disease-driving proteins. However, the effectiveness of peptide-based cancer therapies is being questioned in light of declines in pharmaceutical R&D efficiency. As a model of whole organism, zebrafish provide a means to develop promising peptide and protein anticancer agents in an informative, cost-effective and time-efficient manner, which also allows for surveying mechanisms of drug action and optimization of drug delivery system...
March 18, 2017: Amino Acids
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