Approved drugs are to be studied for use in Alzheimer's disease.

BMJ. 2016 Sep 19;354:i5063

Authors: Hopkins Tanne J

PMID: 27644990 [PubMed - indexed for MEDLINE]

The anti-Aspergillus drug pipeline: Is the glass half full or empty?

Med Mycol. 2017 Jan 01;55(1):118-124

Authors: Osherov N, Kontoyiannis DP

Abstract
Aspergillosis has emerged as important human mycoses, in view of the ever expanding population at risk. The emergence of resistance to the most commonly used drugs for aspergillosis, the azoles, the mediocre activity, and frequent toxicity of the current antifungal armamentarium, support the need for development of novel antifungals for treatment of this disease. In this minireview, we describe recent efforts by small drug companies and University research labs to develop novel therapies for invasive aspergillus infections. We specifically discuss four small-molecule antifungals (T-2307, E1210/APX001, ASP2397, and F901318) with novel modes-of-action, which are currently entering phase I clinical trials. In addition, we provide a nonexhaustive discussion of some interesting, yet early developments in the quest for improved therapeutic strategies such as (i) novel formulations of amphotericin B including AMB nanoparticle suspensions and AMB-arabinogalactan or AMB-PEG conjugates that show low toxicity and high efficacy in preclinical animal models, (ii) repurposed drugs that synergize with existing antifungals (clozafimine, trichostatin A, MGCD290, geldanamycin, tacrolimus, cyclosporin), (iii) natural products (psoriasin, humidimycin), and (iv) immunotherapy using adoptive transfer of activated immune cells with antifungal activity. We argue that despite the plethora of candidates, the extremely low success rates of drug development leading to clinically useful drugs reinforces the need for continued clinical reliance on mainstream antifungals and their improved derivatives.

PMID: 27562862 [PubMed - indexed for MEDLINE]

Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments.

ChemMedChem. 2016 Jun 20;11(12):1259-63

Authors: Bottegoni G, Veronesi M, Bisignano P, Kacker P, Favia AD, Cavalli A

Abstract
In this study, we report on a virtual ligand screening protocol optimized to identify fragments endowed with activity at multiple targets. Thanks to this protocol, we were able to identify a fragment that displays activity in the low-micromolar range at both β-secretase 1 (BACE-1) and glycogen synthase kinase 3β (GSK-3β). These two structurally and physiologically unrelated enzymes likely contribute, through different pathways, to the onset of Alzheimer's disease (AD). Therefore, their simultaneous inhibition holds great potential in exerting a profound effect on AD. In perspective, the strategy outlined herein can be adapted to other target combinations.

PMID: 26663255 [PubMed - indexed for MEDLINE]

A review of network-based approaches to drug repositioning.

Brief Bioinform. 2017 Feb 27;:

Authors: Lotfi Shahreza M, Ghadiri N, Mousavi SR, Varshosaz J, Green JR

Abstract
Experimental drug development is time-consuming, expensive and limited to a relatively small number of targets. However, recent studies show that repositioning of existing drugs can function more efficiently than de novo experimental drug development to minimize costs and risks. Previous studies have proven that network analysis is a versatile platform for this purpose, as the biological networks are used to model interactions between many different biological concepts. The present study is an attempt to review network-based methods in predicting drug targets for drug repositioning. For each method, the preferred type of data set is described, and their advantages and limitations are discussed. For each method, we seek to provide a brief description, as well as an evaluation based on its performance metrics.We conclude that integrating distinct and complementary data should be used because each type of data set reveals a unique aspect of information about an organism. We also suggest that applying a standard set of evaluation metrics and data sets would be essential in this fast-growing research domain.

PMID: 28334136 [PubMed - as supplied by publisher]

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase.

Sci Rep. 2017 Mar 21;7:44912

Authors: Segura-Cabrera A, Tripathi R, Zhang X, Gui L, Chou TF, Komurov K

Abstract
Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

PMID: 28322292 [PubMed - in process]

Computational Drug Repositioning Using Continuous Self-Controlled Case Series.

KDD. 2016 Aug;2016:491-500

Authors: Kuang Z, Thomson J, Caldwell M, Peissig P, Stewart R, Page D

Abstract
Computational Drug Repositioning (CDR) is the task of discovering potential new indications for existing drugs by mining large-scale heterogeneous drug-related data sources. Leveraging the patient-level temporal ordering information between numeric physiological measurements and various drug prescriptions provided in Electronic Health Records (EHRs), we propose a Continuous Self-controlled Case Series (CSCCS) model for CDR. As an initial evaluation, we look for drugs that can control Fasting Blood Glucose (FBG) level in our experiments. Applying CSCCS to the Marshfield Clinic EHR, well-known drugs that are indicated for controlling blood glucose level are rediscovered. Furthermore, some drugs with recent literature support for the potential effect of blood glucose level control are also identified.

PMID: 28316874 [PubMed - in process]

Integrative cancer pharmacogenomics to infer large-scale drug taxonomy.

Cancer Res. 2017 Mar 17;:

Authors: El-Hachem N, Gendoo DM, Soltan Ghoraie L, Safikhani Z, Smirnov P, Chung C, Deng K, Fang A, Birkwood E, Ho C, Isserlin R, Bader G, Goldenberg A, Haibe-Kains B

Abstract
Identification of drug targets and mechanism of action (MoA) for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Current MoA prediction largely relies on prior information including side effects, therapeutic indication, and chemo-informatics. Such information is not transferable or applicable for newly identified, previously uncharacterized small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary towards development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose here a new integrative computational pharmacogenomic approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that relies only on basic drug characteristics towards elucidating drug-drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation, and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. DNF taxonomy succeeded in identifying pertinent and novel drug-drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. The scalability of DNF facilitated identification of key drug relationships across different drug categories and poses as a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on compound MoA and potential insights for drug repurposing.

PMID: 28314784 [PubMed - as supplied by publisher]

Repositioning of anti-viral drugs as therapy for cervical cancer.

Pharmacol Rep. 2016 Oct;68(5):983-9

Authors: Sharma S, Baksi R, Agarwal M

Abstract
BACKGROUND: Increase in expression of eIF4E (Eukaryotic translation initiation factor 4E) protein is mediated by oncogenic proteins of Human Papilloma Virus (HPV). Increased expression of eIF4E plays an important role in HPV induced carcinogenesis. Ribavirin and Indinavir are known inhibitors of eIF4E activity.
METHODS: The effect of the drugs on HeLa cells was assessed by in vitro assays including cell viability using MTT and Neutral red assay, apoptotic potential using Caspase-3, Caspase-8 and Caspase-9 activity assays and MMP-2 and MMP-9 secretion by determination of Gelatinase activity. The in vivo effect of Ribavirin treatment on tumor volume was assessed in human xenograft in immunocompromised C57BL/6 mice.
RESULTS: In vitro analyses indicate that Ribavirin and Indinavir reduce viability of HeLa cells, induce apoptosis and decrease secretion of MMPs. Treatment with Ribavirin at a dose of 50mg/kg and 100mg/kg daily led to significant decrease in tumor volume in vivo.
CONCLUSION: The study thus provides evidence that Ribavirin and Indinavir can be explored as therapy against HPV-18 induced cervical cancer.

PMID: 27379616 [PubMed - indexed for MEDLINE]

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

PLoS Negl Trop Dis. 2017 Mar 17;11(3):e0005472

Authors: Reigada C, Valera-Vera EA, Sayé M, Errasti AE, Avila CC, Miranda MR, Pereira CA

Abstract
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6-10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

PMID: 28306713 [PubMed - as supplied by publisher]

Heter-LP: A heterogeneous label propagation algorithm and its application in drug repositioning.

J Biomed Inform. 2017 Mar 11;:

Authors: Lotfi Shahreza M, Ghadiri N, Rasoul Mousavi S, Varshosaz J, Green JR

Abstract
Drug repositioning offers an effective solution to drug discovery, saving both time and resources by finding new indications for existing drugs. Typically, a drug takes effect via its protein targets in the cell. As a result, it is necessary for drug development studies to conduct an investigation into the interrelationships of drugs, protein targets, and diseases. Although previous studies have made a strong case for the effectiveness of integrative network-based methods for predicting these interrelationships, little progress has been achieved in this regard within drug repositioning research. Moreover, the interactions of new drugs and targets (lacking any known targets and drugs, respectively) cannot be accurately predicted by most established methods. In this paper, we propose a novel semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration. To predict drug-target, disease-target, and drug-disease associations, we use information about drugs, diseases, and targets as collected from multiple sources at different levels. Our algorithm integrates these various types of data into a heterogeneous network and implements a label propagation algorithm to find new interactions. Statistical analyses of 10-fold cross-validation results and experimental analyses support the effectiveness of the proposed algorithm.

PMID: 28300647 [PubMed - as supplied by publisher]

FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model.

J Transl Med. 2017 Mar 15;15(1):58

Authors: Szymiczek A, Pastorino S, Larson D, Tanji M, Pellegrini L, Xue J, Li S, Giorgi C, Pinton P, Takinishi Y, Pass HI, Furuya H, Gaudino G, Napolitano A, Carbone M, Yang H

Abstract
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.
METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo.
RESULTS: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity.
CONCLUSIONS: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.

PMID: 28298211 [PubMed - in process]

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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7 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 2017/03/14

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.

Computational Discovery of Niclosamide Ethanolamine, A Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells in Vitro and in Mice by Inhibiting CDC37 Signaling.

Gastroenterology. 2017 Mar 08;:

Authors: Chen B, Wei W, Ma L, Yang B, Gill RM, Chua MS, Butte AJ, So S

Abstract
BACKGROUND & AIMS: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC).
METHODS: We searched public databases of mRNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are downregulated in HCCs and reduce expression of genes upregulated in HCCs using a non-parametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In 1 model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated beta catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored.
RESULTS: Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more toxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes downregulated in HCC and reduced expression of 29 genes upregulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-beta catenin, STAT3, AKT-mTOR, EGFR-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 (CDC37) protein and disrupt its interaction with heat shock protein 90 (HSP90).
CONCLUSIONS: In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between CDC37 and HSP90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC.

PMID: 28284560 [PubMed - as supplied by publisher]

Support for phosphoinositol 3 kinase and mTOR inhibitors as treatment for lupus using in-silico drug-repurposing analysis.

Arthritis Res Ther. 2017 Mar 11;19(1):54

Authors: Toro-Domínguez D, Carmona-Sáez P, Alarcón-Riquelme ME

Abstract
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with few treatment options. Current therapies are not fully effective and show highly variable responses. In this regard, large efforts have focused on developing more effective therapeutic strategies. Drug repurposing based on the comparison of gene expression signatures is an effective technique for the identification of new therapeutic approaches. Here we present a drug-repurposing exploratory analysis using gene expression signatures from SLE patients to discover potential new drug candidates and target genes.
METHODS: We collected a compendium of gene expression signatures comprising peripheral blood cells and different separate blood cell types from SLE patients. The Lincscloud database was mined to link SLE signatures with drugs, gene knock-down, and knock-in expression signatures. The derived dataset was analyzed in order to identify compounds, genes, and pathways that were significantly correlated with SLE gene expression signatures.
RESULTS: We obtained a list of drugs that showed an inverse correlation with SLE gene expression signatures as well as a set of potential target genes and their associated biological pathways. The list includes drugs never or little studied in the context of SLE treatment, as well as recently studied compounds.
CONCLUSION: Our exploratory analysis provides evidence that phosphoinositol 3 kinase and mammalian target of rapamycin (mTOR) inhibitors could be potential therapeutic options in SLE worth further future testing.

PMID: 28284231 [PubMed - in process]

MOST: most-similar ligand based approach to target prediction.

BMC Bioinformatics. 2017 Mar 11;18(1):165

Authors: Huang T, Mi H, Lin CY, Zhao L, Zhong LL, Liu FB, Zhang G, Lu AP, Bian ZX, for MZRW Group

Abstract
BACKGROUND: Many computational approaches have been used for target prediction, including machine learning, reverse docking, bioactivity spectra analysis, and chemical similarity searching. Recent studies have suggested that chemical similarity searching may be driven by the most-similar ligand. However, the extent of bioactivity of most-similar ligands has been oversimplified or even neglected in these studies, and this has impaired the prediction power.
RESULTS: Here we propose the MOst-Similar ligand-based Target inference approach, namely MOST, which uses fingerprint similarity and explicit bioactivity of the most-similar ligands to predict targets of the query compound. Performance of MOST was evaluated by using combinations of different fingerprint schemes, machine learning methods, and bioactivity representations. In sevenfold cross-validation with a benchmark Ki dataset from CHEMBL release 19 containing 61,937 bioactivity data of 173 human targets, MOST achieved high average prediction accuracy (0.95 for pKi ≥ 5, and 0.87 for pKi ≥ 6). Morgan fingerprint was shown to be slightly better than FP2. Logistic Regression and Random Forest methods performed better than Naïve Bayes. In a temporal validation, the Ki dataset from CHEMBL19 were used to train models and predict the bioactivity of newly deposited ligands in CHEMBL20. MOST also performed well with high accuracy (0.90 for pKi ≥ 5, and 0.76 for pKi ≥ 6), when Logistic Regression and Morgan fingerprint were employed. Furthermore, the p values associated with explicit bioactivity were found be a robust index for removing false positive predictions. Implicit bioactivity did not offer this capability. Finally, p values generated with Logistic Regression, Morgan fingerprint and explicit activity were integrated with a false discovery rate (FDR) control procedure to reduce false positives in multiple-target prediction scenario, and the success of this strategy it was demonstrated with a case of fluanisone. In the case of aloe-emodin's laxative effect, MOST predicted that acetylcholinesterase was the mechanism-of-action target; in vivo studies validated this prediction.
CONCLUSIONS: Using the MOST approach can result in highly accurate and robust target prediction. Integrated with a FDR control procedure, MOST provides a reliable framework for multiple-target inference. It has prospective applications in drug repurposing and mechanism-of-action target prediction.

PMID: 28284192 [PubMed - in process]

Topical phenytoin for the treatment of neuropathic pain.

J Pain Res. 2017;10:469-473

Authors: Kopsky DJ, Keppel Hesselink JM

Abstract
We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches (e.g., lidocaine 5% patches) have complex handling, especially for geriatric patients. Only in a few countries, compounded creams based on tricyclic antidepressants or other (co-)analgesics are available. Such topical analgesic creams, however, are easy to administer and have a low propensity for inducing side effects. We, therefore, developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain. All patients were refractory to a number of other analgesics. In all patients, phenytoin cream was effective in reducing pain completely, without any side effects, and the tolerability was excellent. The onset of action of the phenytoin creams was within 30 minutes. Phenytoin cream might become a new treatment modality of the treatment of neuropathic pain.

PMID: 28280381 [PubMed - in process]

Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

J Hematol Oncol. 2017 Mar 09;10(1):67

Authors: Yoshida GJ

Abstract
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

PMID: 28279189 [PubMed - in process]

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.

Expert Opin Investig Drugs. 2017 Mar 06;:

Authors: Martinez A, Palomo Ruiz MD, Perez DI, Gil C

Abstract
INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clin ical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert Opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.

PMID: 28277881 [PubMed - as supplied by publisher]

Exploring the epigenetic drug discovery landscape.

Expert Opin Drug Discov. 2017 Feb 28;:1-18

Authors: Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-Umporn C, Malik AA, Schaduangrat N, Seenprachawong K, Wongchitrat P, Supokawej A, Prachayasittikul V, Wikberg JE, Nantasenamat C

Abstract
INTRODUCTION: Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics. Expert opinion: Despite significant interests in targeting epigenetic modifiers as a therapeutic route, certain classes of target proteins are heavily studied while some are less characterized. Thus, such orphan target proteins are not yet druggable with limited report of active modulators. Current research points towards a great future with novel drugs directed to the many complex multifactorial diseases of humans, which are still often poorly understood and difficult to treat.

PMID: 28276705 [PubMed - as supplied by publisher]