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Repurposing drugs

Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
Balasundaram Preethi, Veerappapillai Shanthi, Karuppasamy Ramanathan
BACKGROUND: Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. OBJECTIVE: The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. METHODS: We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones...
October 19, 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
Jyothi Padiadpu, Priyanka Baloni, Kushi Anand, MohamedHusen Munshi, Chandrani Thakur, Abhilash Mohan, Amit Singh, Nagasuma Chandra
The global mechanisms and associated molecular alterations that occur in drug-resistant mycobacteria are poorly understood. To address this, we obtain genomics data and then construct a genome-scale response network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher global alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli, of which redox response was prominent. Using phenotypic profiling, we find that resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses...
September 9, 2016: ACS Infectious Diseases
Nathan B Roberts, Aniket S Wadajkar, Jeffrey A Winkles, Eduardo Davila, Anthony J Kim, Graeme F Woodworth
Glioblastoma (GBM) is a fatal brain cancer for which new treatment options are sorely needed. Platinum-based drugs have been investigated extensively for GBM treatment but few have shown significant efficacy without major central nervous system (CNS) and systemic toxicities. The relative success of platinum drugs for treatment of non-CNS cancers indicates great therapeutic potential when effectively delivered to the tumor region(s). New insights into the broad anticancer effects of platinum drugs, particularly immunomodulatory effects, and innovative delivery strategies that can maximize these multi-modal effects and minimize toxicities may promote the re-purposing of this chemotherapeutic drug class for GBM treatment...
2016: Oncoimmunology
Keertan Dheda, Kwok Chiu Chang, Lorenzo Guglielmetti, Jennifer Furin, H Simon Schaaf, Dumitru Chesov, Aliasgar Esmail, Christoph Lange
Globally there is a burgeoning epidemic of drug mono-resistant tuberculosis (TB), multi-drug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB). Almost 20% of all TB strains worldwide are resistant to at least 1 major TB drug including isoniazid. In several parts of the world there is an increasing incidence of MDR-TB, and alarmingly almost a third of MDR-TB cases globally are resistant to either a fluoroquinolone or aminoglycocide. This trend cannot be ignored because DR-TB is associated with greater morbidity compared to drug-sensitive TB, it accounts for almost 25% of global TB mortality, is extremely costly to treat, consuming substantial portions of budgets allocated to national TB programmes in TB endemic countries, and is a major threat to healthcare workers who are already in short supply in resource-poor settings...
October 15, 2016: Clinical Microbiology and Infection
Le Zhang, Liang Xu, Fengchun Zhang, Erina Vlashi
Experimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory effects on the properties of breast cancer cells and BCSCs, such as mammosphere forming efficiency, invasion, migration, apoptosis, the expression of stem cell markers and epithelial-to-mesenchymal transition (EMT) related markers of breast cancer cells...
October 18, 2016: Cell Cycle
Charbel Moussa
No abstract text is available yet for this article.
October 18, 2016: Expert Review of Neurotherapeutics
Danielle Macedo, Adriano José Maia Chaves Filho, Caren Nádia Soares de Sousa, João Quevedo, Tatiana Barichello, Hélio Vitoriano Nobre Júnior, David Freitas de Lucena
OBJECTIVES: The first drug repurposed for the treatment of depression was the tuberculostatic iproniazid. At present, drugs belonging to new classes of antidepressants still have antimicrobial effects. Dysbiosis of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, the focus of this narrative review is to compile the available studies regarding the influences of gut microbiota in behavior and depression and to show the antimicrobial effect of antidepressant drugs...
September 28, 2016: Journal of Affective Disorders
Zhe Li, Qin Li, Jun Wu, Manyuan Wang, Junxian Yu
Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety...
October 7, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Georgia M Walton, James A Stockley, Diane Griffiths, Charandeep S Sadhra, Thomas Purvis, Elizabeth Sapey
Drug classes used in the treatment of Chronic Obstructive Pulmonary Disease (COPD) have not changed for many years, and none to date have shown disease-modifying activity. Statins are used to help reduce cardiovascular risk, which is high in many patients with COPD. Their use has been associated with improvements in some respiratory manifestations of disease and reduction in all-cause mortality, with greatest reductions seen in patients with the highest inflammatory burden. The mechanism for these effects is poorly understood...
October 11, 2016: Journal of Clinical Medicine
Isabel López-García, Domokos Gerő, Bartosz Szczesny, Petra Szoleczky, Gabor Olah, Katalin Módis, Kangling Zhang, Gao Jungling, Ping Wu, Lawrence C Sowers, Doug DeWitt, Donald S Prough, Csaba Szabo
BACKGROUND AND PURPOSE: We hypothesized that an in vitro, stretch-based model of neural injury may be useful to identify compounds that decrease the cellular damage in neurotrauma. EXPERIMENTAL APPROACH: We screened three neural cell lines (B35, RN33B, SH-SY5Y) subjected to two differentiation methods and selected all-trans-retinoic acid-differentiated B35 rat neuroblastoma cells subjected to rapid stretch injury, coupled with a subthreshold concentration of H2 O2 , for the screen...
October 9, 2016: British Journal of Pharmacology
Hansaim Lim, Aleksandar Poleksic, Yuan Yao, Hanghang Tong, Di He, Luke Zhuang, Patrick Meng, Lei Xie
Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification...
October 2016: PLoS Computational Biology
Antonella Tramutola, Andrea Arena, Chiara Cini, D Allan Butterfield, Eugenio Barone
Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Post-mortem analyses of Alzheimer disease (AD) subjects revealed insulin resistance in the brain, suggesting a role of this condition in cognitive deficits observed in AD. In this review, we focus on the glucagon-like peptide-1 (GLP-1) signaling pathway, whose role in the brain is collecting increasing attention because of its association with insulin signaling activation. Areas covered: The role of GLP-1-mediated effects in the brain and how they are affected along the progression of AD pathology is discussed...
October 7, 2016: Expert Review of Neurotherapeutics
Shankar Thangamani, Hassan E Eldesouky, Haroon Mohammad, Pete E Pascuzzi, Larisa Avramova, Tony R Hazbun, Mohamed N Seleem
BACKGROUND: Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear. METHODS: The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen...
October 3, 2016: Biochimica et Biophysica Acta
Furkan U Ertem, Wenqian Zhang, Kyle Chang, Wan Mohaiza Dashwood, Praveen Rajendran, Deqiang Sun, Ala Abudayyeh, Eduardo Vilar, Maen Abdelrahim, Roderick H Dashwood
Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac...
October 5, 2016: International Journal of Cancer. Journal International du Cancer
Yvonne S Yang, Stephen R Marder, Michael F Green
Currently-approved treatments for schizophrenia only minimally affect the cognitive features of the illness that are the most closely related to disability. Hence, there is now considerable effort to repurpose drugs for schizophrenia, and to seek agents that can improve cognition by targeting receptor systems other than the dopaminergic system. The results of these studies have been mixed thus far, however this continues to be a high-priority area of schizophrenia research and an important unmet need. This article is protected by copyright...
October 5, 2016: Clinical Pharmacology and Therapeutics
Yang Chen, Rong Xu
A recent multi-platform analysis by The Cancer Genome Atlas identified four distinct molecular subtypes for glioblastoma (GBM) and demonstrated that the subtypes correlate with clinical phenotypes and treatment responses. In this study, we developed a computational drug repurposing approach to predict GBM drugs based on the molecular subtypes. Our approach leverages the genomic signature for each GBM subtype, and integrates the human cancer genomics with mouse phenotype data to identify the opportunity of reusing the FDA-approved agents to treat specific GBM subtypes...
September 30, 2016: Journal of Biomedical Informatics
Marco Scianna, Luca Munaron
BACKGROUND: Cancer is a heterogeneous disease, which is based on an intricate network of processes at different spatiotemporal scales, from the genome to the tissue level. Hence the necessity for the biomedical and pharmaceutical research to work in a multiscale fashion. In this respect, a significant help derives from the collaboration with theoretical sciences. Indeed, mathematical models can provide insights into tumor-related processes and support clinical oncologists in the design of treatment regime, dosage, schedule and toxicity...
October 3, 2016: Recent Patents on Anti-cancer Drug Discovery
Valerie W C Soo, Brian W Kwan, Héctor Quezada, Israel Castillo-Juárez, Berenice Pérez-Eretza, Silvia Julieta García-Contreras, Mariano Martínez-Vázquez, Thomas K Wood, Rodolfo García-Contreras
Despite the fact that bacterial infections are one of the leading causes of death worldwide and that mortality rates are increasing at alarming rates, no new antibiotics have been produced by the pharmaceutical industry in more than a decade. The situation is so dire that the World Health Organization warned that we may enter a "post-antibiotic era" within this century; accordingly, bacteria resistant against all known antibiotics are becoming common and already producing untreatable infections. Although several novel approaches to combat bacterial infections have been proposed, they have yet to be implemented in clinical practice...
September 30, 2016: Current Topics in Medicinal Chemistry
Jörn Lötsch, Alfred Ultsch
OBJECTIVE: The public accessibility of "big data" about the molecular targets of drugs and the biological functions of genes allows novel data science-based approaches to pharmacology that link drugs directly with their effects on pathophysiologic processes. This provides a phenotypic path to drug discovery and repurposing. This paper compares the performance of a functional genomics-based criterion to the traditional drug target-based classification. METHODS: Knowledge discovery in the DrugBank and Gene Ontology databases allowed the construction of a "drug target versus biological process" matrix as a combination of "drug versus genes" and "genes versus biological processes" matrices...
October 1, 2016: European Journal of Clinical Pharmacology
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