Enforceability of second medical use claims in the UK.

Pharm Pat Anal. 2017 09;6(5):193-195

Authors: Carver T

PMID: 28818024 [PubMed - indexed for MEDLINE]

Computational biology: future challenges for the patenting of repurposed drugs.

Pharm Pat Anal. 2017 09;6(5):201-203

Authors: Bloom B

PMID: 28818005 [PubMed - indexed for MEDLINE]

Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly.

Acta Biomater. 2018 03 01;68:113-124

Authors: He H, Markoutsa E, Li J, Xu P

Abstract
Disulfiram (DSF), an FDA approved drug for the treatment of alcoholism, degrades to therapeutically active diethyldithiocarbamate (DDTC) in the body by reduction. Hereby, we developed a redox sensitive DDTC-polymer conjugate for targeted cancer therapy. It was found that the DDTC-polymer conjugate modified with a β-d-galactose receptor targeting ligand can self-assemble into LDNP nanoparticle and efficiently enter cancer cells by receptor-mediated endocytosis. Upon cellular uptake, the LDNP nanoparticle degrades and releases DDTC due to the cleavage of disulfide bonds, and subsequently forms copper (II) DDTC complex to kill a broad spectrum of cancer cells. 3D cell culture revealed that this nanoparticle shows much stronger tumor mass penetrating and destructive capacity. Furthermore, LDNP nanoparticles exhibited much greater potency in inhibiting tumor growth in a peritoneal metastatic ovarian tumor model.
STATEMENT OF SIGNIFICANCE: The β-d-galactose receptor targeted disulfiram loaded nanoparticle (LDNP) is novel in the following aspects.

PMID: 29294377 [PubMed - indexed for MEDLINE]

The potential for repositioning antithyroid agents as antiasthma drugs.

J Allergy Clin Immunol. 2016 11;138(5):1458-1461.e8

Authors: Suzuki S, Ogawa M, Ohta S, Arima K, Nunomura S, Nanri Y, Mitamura Y, Yoshihara T, Nakamura Y, Yamauchi K, Chibana K, Ishii Y, Lee JJ, Aratani Y, Kakuta S, Kubo S, Iwakura Y, Yoshida H, Izuhara K

PMID: 27444178 [PubMed - indexed for MEDLINE]

Mebendazole stimulates CD14+ myeloid cells to enhance T-cell activation and tumour cell killing.

Oncotarget. 2018 Jul 20;9(56):30805-30813

Authors: Rubin J, Mansoori S, Blom K, Berglund M, Lenhammar L, Andersson C, Loskog A, Fryknäs M, Nygren P, Larsson R

Abstract
Mebendazole (MBZ) was recently shown to induce a tumor suppressive M1 phenotype in THP-1 monocytes and macrophages. In the present study the immune effects of MBZ was further investigated using human peripheral blood mononuclear cells (PBMCs) co-cultured with tumour cells. The Biomap platform was used to screen for biomarkers induced from MBZ exposed co-cultures of T-cell receptor activated PBMCs, HT29 colon cancer cells and either human fibroblasts or human umbilical vein endothelial cells (HUVEC) cells. In these co-culture systems MBZ at 0.3-10 μM induced significant increases in TNFα and IFNγ indicating immune stimulation. PBMC cultures alone were subsequently tested for activation status and only in PBMCs activated by CD3/IL2 stimulation and MBZ, at a clinically achievable concentration, was able to increase PBMC clustering and release of pro-inflammatory IFNγ, TNFα, IL6 and IL1β cytokines. Moreover, when PBMC cultures were functionally tested for immune cell killing of lung cancer A549NucLightRed cells, MBZ significantly increased tumour cell apoptosis and reduced the number of surviving tumour cells. This effect was dependent on the presence of CD14 monocytes/macrophages in the co-culture. In summary, MBZ potentiated the immune stimulatory and anticancer effects of anti-CD3/IL2 activated PBMCs which could be relevant to explain the anticancer activity of MBZ observed in the clinic.

PMID: 30112108 [PubMed]

Revisiting Connectivity Map from a gene co-expression network analysis.

Exp Ther Med. 2018 Aug;16(2):493-500

Authors: Liu W, Tu W, Li L, Liu Y, Wang S, Li L, Tao H, He H

Abstract
The Connectivity Map (CMap) is a tool that has been extensively utilized to study drug repositioning and side-effect prediction. However, most of these analyses rely on signature genes, ignoring the pathways by which those genes are regulated, as well as the functional overlap of redundant genes. The present study utilized a systems biology approach referred to as Weighted Gene Co-expression Network Analysis (WGCNA) to dissect the transcriptional profiles of CMap and reveal these hidden factors. Seven common modules associated with protein binding, extracellular matrix organization and translation were identified. Furthermore, drugs were clustered based on module expression to infer their mechanism of action (MoA) based on common activity profiles. As an extension of this, an example of disease-based module projection to identify novel drugs was provided. The analysis developed in the present study may provide a novel framework for drug repositioning or discovering MoAs.

PMID: 30112021 [PubMed]

Combined analysis of gene expression and genome binding profiles identified potential therapeutic targets of ciclopirox in Ewing sarcoma.

Mol Med Rep. 2018 Mar;17(3):4291-4298

Authors: Yuan B, Ji W, Xia H, Li J

Abstract
Ciclopirox (CPX) is a synthetic antifungal drug that is mainly used to treat dermatomycoses. The aim of the present study was to determine whether CPX could influence Ewing sarcoma progression. The present study suggested that CPX treatment may inhibit Ewing sarcoma (ES) progression through Ewing sarcoma breakpoint region 1‑Friend leukemia integration 1 (EWS‑FLI1), a common fusion transcript structure in patients with ES. To determine the underlying mechanisms of ES progression, cross analysis was conducted on three high‑throughput genome or transcript me datasets from the Gene Expression Omnibus. The results indicated that CPX may inhibit ES growth by affecting vasculature development and DNA replication. A combination of genome‑wide expression and binding profiles revealed several potential targets for CPX in ES, including collagen type I α2 chain, N‑myc proto‑oncogene and transforming growth factor β1, which contained significantly enriched binding peaks of FLI1. In addition, network analysis, including a protein‑protein interaction network and a transcription regulatory network, provided further detailed information about the roles of CPX in ES. This study may provide a novel solution for ES treatment and may also aid in improving its prognosis.

PMID: 29328472 [PubMed - indexed for MEDLINE]

Novel lead compounds in pre-clinical development against African sleeping sickness.

Medchemcomm. 2017 Oct 01;8(10):1872-1890

Authors: Berninger M, Schmidt I, Ponte-Sucre A, Holzgrabe U

Abstract
Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus Trypanosoma. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to e.g. toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development against HAT are considered, namely the target-based approach, the phenotypic high throughput screening and the drug repurposing strategy. The most promising compounds emerging from these approaches entering an in vivo evaluation are mentioned herein. Of note, it may turn out to be difficult to confirm in vitro activity in an animal model of infection; however, possible reasons for the missing efficacy in unsuccessful in vivo studies are discussed.

PMID: 30108710 [PubMed]

Tetracycline repurposing in neurodegeneration: focus on Parkinson's disease.

J Neural Transm (Vienna). 2018 Aug 14;:

Authors: Bortolanza M, Nascimento GC, Socias SB, Ploper D, Chehín RN, Raisman-Vozari R, Del-Bel E

Abstract
The prevalence of Parkinson's disease, which affects millions of people worldwide, is increasing due to the aging population. In addition to the classic motor symptoms caused by the death of dopaminergic neurons, Parkinson's disease encompasses a wide range of nonmotor symptoms. Although novel disease-modifying medications that slow or stop Parkinson's disease progression are being developed, drug repurposing, which is the use of existing drugs that have passed numerous toxicity and clinical safety tests for new indications, can be used to identify treatment compounds. This strategy has revealed that tetracyclines are promising candidates for the treatment of Parkinson's disease. Tetracyclines, which are neuroprotective, inhibit proinflammatory molecule production, matrix metalloproteinase activity, mitochondrial dysfunction, protein misfolding/aggregation, and microglial activation. Two commonly used semisynthetic second-generation tetracycline derivatives, minocycline and doxycycline, exhibit effective neuroprotective activity in experimental models of neurodegenerative/ neuropsychiatric diseases and no substantial toxicity. Moreover, novel synthetic tetracyclines with different biological properties due to chemical tuning are now available. In this review, we discuss the multiple effects and clinical properties of tetracyclines and their potential use in Parkinson's disease treatment. In addition, we examine the hypothesis that the anti-inflammatory activities of tetracyclines regulate inflammasome signaling. Based on their excellent safety profiles in humans from their use for over 50 years as antibiotics, we propose the repurposing of tetracyclines, a multitarget antibiotic, to treat Parkinson's disease.

PMID: 30109452 [PubMed - as supplied by publisher]

Drug repurposing for neuroregeneration in multiple sclerosis.

Neural Regen Res. 2018 Aug;13(8):1366-1367

Authors: Küry P, Kremer D, Göttle P

PMID: 30106047 [PubMed]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/08/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Molecular Property Diagnostic Suite for Diabetes Mellitus (MPDSDM): An Integrated Web Portal for Drug Discovery and Drug Repurposing.

J Biomed Inform. 2018 Aug 06;:

Authors: Singh Gaur A, Nagamani S, Tanneeru K, Druzhilovskiy D, Rudik A, Poroikov V, Narahari Sastry G

Abstract
Molecular Property Diagnostic Suite - Diabetes Mellitus (MPDSDM) is a Galaxy-based, open source disease-specific web portal for diabetes. It consists of three modules namely i) data library ii) data processing and iii) data analysis tools. The data library (target library and literature) module provide extensive and curated information about the genes involved in type 1 and type 2 diabetes onset and progression stage (available at http://www.mpds-diabetes.in). The database also contains information on drug targets, biomarkers, therapeutics and associated genes specific to type 1, and type 2 diabetes. A unique MPDS identification number has been assigned for each gene involved in diabetes mellitus and the corresponding card contains chromosomal data, gene information, protein UniProt ID, functional domains, druggability and related pathway information. One of the objectives of the web portal is to have an open source data repository that contains all information on diabetes and use this information for developing therapeutics to cure diabetes. We also make an attempt for computational drug repurposing for the validated diabetes targets. We performed virtual screening of 1455 FDA approved drugs on selected 20 type 1 and type 2 diabetes proteins using docking protocol and their biological activity was predicted using "PASS Online" server (http://www.way2drug.com/passonline) towards anti-diabetic activity, resulted in the identification of 41 drug molecules. Five drug molecules (which are earlier known for anti-malarial/microbial, anti-viral, anti-cancer, anti-pulmonary activities) were proposed to have a better repurposing potential for type 2 anti-diabetic activity and good binding affinity towards type 2 diabetes target proteins.

PMID: 30092360 [PubMed - as supplied by publisher]

Use of metformin and survival of patients with high-grade glioma.

Int J Cancer. 2018 Aug 09;:

Authors: Seliger C, Luber C, Gerken M, Schaertl J, Proescholdt M, Riemenschneider MJ, Meier CR, Bogdahn U, Leitzmann MF, Klinkhammer-Schalke M, Hau P

Abstract
High-grade glioma (HGG) is associated with poor prognosis. Drug repurposing evolves as new modality to improve standard therapy. The antidiabetic drug metformin has been found to inhibit glioma cell growth in vitro and in vivo. The aim of the present retrospective cohort study was to evaluate the survival of patients with HGG with or without treatment with metformin, based on a large cohort of a cancer registry. The analysis included 1,093 patients with HGG diagnosed between 1998 and 2013 from the population based clinical cancer registry Regensburg (Germany), which covers 2.1 Mio inhabitants and 98% of all cancer diagnoses. We performed multivariable adjusted Cox-regression analyses. Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) of patients with HGG with or without treatment with metformin were obtained. Use of metformin was associated with a significantly better overall and progression-free survival of patients with WHO grade III glioma (HR for OS=0.30; 95% CI=0.11-0.81, HR for PFS=0.29; 95% CI=0.11-0.78), while there were no significant relations with OS (HR=0.83; 95% CI=0.57-1.20) or PFS (HR=0.85; 95% CI=0.59-1.22) in patients with WHO grade IV glioma. In conclusion, use of metformin is associated with better overall and progression-free survival of patients with WHO grade III. Possible underlying mechanisms include the higher prevalence of IDH mutations in WHO grade III glioma, which might sensitize to the metabolic drug metformin. This article is protected by copyright. All rights reserved.

PMID: 30091464 [PubMed - as supplied by publisher]

Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery.

Front Chem. 2018;6:315

Authors: Kumar A, Zhang KYJ

Abstract
Molecular similarity is a key concept in drug discovery. It is based on the assumption that structurally similar molecules frequently have similar properties. Assessment of similarity between small molecules has been highly effective in the discovery and development of various drugs. Especially, two-dimensional (2D) similarity approaches have been quite popular due to their simplicity, accuracy and efficiency. Recently, the focus has been shifted toward the development of methods involving the representation and comparison of three-dimensional (3D) conformation of small molecules. Among the 3D similarity methods, evaluation of shape similarity is now gaining attention for its application not only in virtual screening but also in molecular target prediction, drug repurposing and scaffold hopping. A wide range of methods have been developed to describe molecular shape and to determine the shape similarity between small molecules. The most widely used methods include atom distance-based methods, surface-based approaches such as spherical harmonics and 3D Zernike descriptors, atom-centered Gaussian overlay based representations. Several of these methods demonstrated excellent virtual screening performance not only retrospectively but also prospectively. In addition to methods assessing the similarity between small molecules, shape similarity approaches have been developed to compare shapes of protein structures and binding pockets. Additionally, shape comparisons between atomic models and 3D density maps allowed the fitting of atomic models into cryo-electron microscopy maps. This review aims to summarize the methodological advances in shape similarity assessment highlighting advantages, disadvantages and their application in drug discovery.

PMID: 30090808 [PubMed]

Therapeutic Effect of Repurposed Temsirolimus in Lung Adenocarcinoma Model.

Front Pharmacol. 2018;9:778

Authors: Chang HW, Wu MJ, Lin ZM, Wang CY, Cheng SY, Lin YK, Chow YH, Ch'ang HJ, Chang VHS

Abstract
Lung cancer is one of the major cause of cancer-related deaths worldwide. The poor prognosis and resistance to both radiation and chemotherapy urged the development of potential targets for lung cancer treatment. In this study, using a network-based cellular signature bioinformatics approach, we repurposed a clinically approved mTOR inhibitor for renal cell carcinomans, temsirolimus, as the potential therapeutic candidate for lung adenocarcinoma. The PI3K-AKT-mTOR pathway is known as one of the most frequently dysregulated pathway in cancers, including non-small-cell lung cancer. By using a well-documented lung adenocarcinoma mouse model of human pathophysiology, we examined the effect of temsirolimus on the growth of lung adenocarcinoma in vitro and in vivo. In addition, temsirolimus combined with reduced doses of cisplatin and gemcitabine significantly inhibited the lung tumor growth in the lung adenocarcinoma mouse model compared with the temsirolimus alone or the conventional cisplatin-gemcitabine combination. Functional imaging techniques and microscopic analyses were used to reveal the response mechanisms. Extensive immunohistochemical analyses were used to demonstrate the apparent effects of combined treatments on tumor architecture, vasculature, apoptosis, and the mTOR-pathway. The present findings urge the further exploration of temsirolimus in combination with chemotherapy for treating lung adenocarcinoma.

PMID: 30087612 [PubMed]

Network-based drug repositioning: A novel strategy for discovering potential antidepressants and their mode of action.

Eur Neuropsychopharmacol. 2018 Aug 04;:

Authors: Zhang TT, Xue R, Wang X, Zhao SW, An L, Li YF, Zhang YZ, Li S

Abstract
Current target-oriented paradigm for novel antidepressant discovery has been difficult to succeed and the failures always bring huge economic losses. Although abundant ledge of disease related genes and drug action targets has been accumulated, the successful application of the knowledge for new drug discovery is limited. Here, we predicted and validated potential antidepressants and molecular targets from DrugBank recorded drugs using a novel network-based drug repositioning approach. This approach predicted relationships between drug and targets through network-based integration of drug chemical similarity, therapeutic similarity and protein-protein interactions. We predicted genome-wide relations of drugs and targets, and then screened drugs that connect to depression-related targets of known antidepressants. Six drugs were predicted and experimentally validated to have antidepressant-like effects in the tail suspension test (TST) and forced swimming test (FST) in mice. Alverine, which is a gastrointestinal antispasmodic drug, was further validated to display antidepressant-like effects in the learned helplessness and chronic unpredictable stress models of depression. Four targets, including serotonin transporter, norepinephrine transporter, serotonin 1A receptor and serotonin 2A receptor, were included in the predictable system and confirmed as primary sites of action for alverine. The results suggest that alverine may be an effective antidepressant drug and the network-based drug repositioning may be a promising drug discovery paradigm for complex multi-genetic diseases such as depression.

PMID: 30087074 [PubMed - as supplied by publisher]

Future perspectives for cryptococcosis treatment.

Expert Opin Ther Pat. 2018 Aug 07;:1-10

Authors: Santos-Gandelman J, Rodrigues ML, Machado Silva A

Abstract
INTRODUCTION: Cryptococcosis is one of the most devastating human fungal infections. Despite its impact, none of the standard antifungals were developed after 1990. New, improved, less toxic, affordable and widely available treatment is, therefore, imperative. Areas covered: This review offers an insight into technological developments for cryptococcosis disclosed in patent literature. From a broad search of patent documents claiming cryptococcosis treatment and having earliest priority between 1995 and 2015, we selected and summarized compounds/molecules (i) revealed in documents disclosing in vivo activity against Cryptococcus spp. or (ii) found in the pipeline of companies that appeared as assignees in our patent search. This information was complemented with data on compounds under development for this indication from the database Integrity (Clarivate Analytics). Expert opinion: This review demonstrates that drug development against cryptococcosis is discrete. However, it also shows that the existing development is not focused on a single class of molecules, but on different types of molecules with distinct fungal targets, reflecting the complexity of generating novel anti-cryptococcal tools. Given the intrinsic difficulties and high costs of drug development and the evident market failure in this field, we consider drug repurposing the most promising avenue for cryptococcosis treatment.

PMID: 30084284 [PubMed - as supplied by publisher]

Structure Investigation, Enrichment Analysis and Structure-based Repurposing of FDA-approved Drugs as Inhibitors of BET-BRD4.

J Biomol Struct Dyn. 2018 Aug 06;:1-22

Authors: Padmaja D W, Velayutham R, Roy KK

Abstract
We report herein detailed structural insights into the ligand recognition modes guiding bromodomain selectivity, enrichment analysis and docking-based database screening for the identification of the FDA-approved drugs that have potential to be the human BRD4 inhibitors. Analysis of multiple X-ray structures prevailed that the lysine-recognition sites are highly conserved, and apparently, the dynamic ZA loop guides the specific ligand-recognition. The protein-ligand interaction profiling revealed that both BRD2 and BRD4 shared hydrophobic interaction of bound ligands with PRO-98/PRO-82, PHE-99/PHE-83, LEU-108/LEU-92, and direct H-bonding with ASN-156/ASN-140 (BRD2/BRD4), while on the other hand the water-mediated H-bonding of bound ligands with PRO-82, GLN-85, PRO-86, VAL-87, ASP-88, LEU-92, TYR-97 and MET-132, and aromatic π - π stacking with TRP-81 prevailed as unique interaction in BRD4, and were not observed in BRD2. Subsequently, through ROC curve analysis, the best enrichment was found with PDB-ID 4QZS of BRD4 structures. Finally, through docking-based database screening study, we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of -9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry. These insights may serve as basis for structure-based drug design, drug repurposing and the discovery of novel BRD4 inhibitors.

PMID: 30079805 [PubMed - as supplied by publisher]

Fluvastatin activates sirtuin 6 to regulate sterol regulatory element-binding proteins and AMP-activated protein kinase in HepG2 cells.

Biochem Biophys Res Commun. 2018 Aug 02;:

Authors: Kim JH, Lee JM, Kim JH, Kim KR

Abstract
Sirtuins, a family of NAD+-dependent deacetylase enzymes, have been identified as mammalian homologs of yeast silent information regulator 2 (SIR2). Sirtuin 6 (SIRT6) plays important roles in cell homeostasis, DNA damage repair, cancer suppression, and aging. SIRT6 overexpression improves metabolic diseases, such as hypercholesterolemia, cholesterol-related disease, and type 2 diabetes via AMP-activated protein kinase (AMPK) activation. SIRT6 is abundant in the liver and is a crucial target for patients with liver steatosis. Compounds for drug repositioning were screened to identify potential SIRT6 activators, and fluvastatin, a synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase that reduces cholesterol synthesis, was identified to activate SIRT6. When HepG2 cells were treated with fluvastatin, the expression of SIRT6 and phosphorylation of sterol regulatory element-binding protein (SREBP)-1 and AMPKα, which is regulated by SIRT6, increased. In this study, we examined the mechanism underlying cholesterol regulation by fluvastatin via SREBP-1 and AMPKα pathway and suggested that fluvastatin is an SIRT6 activator that regulates cholesterol homeostasis and fatty liver disease.

PMID: 30078674 [PubMed - as supplied by publisher]