Drosophila SMN2 minigene reporter model identifies moxifloxacin as a candidate therapy for SMA.

FASEB J. 2019 Dec 31;:

Authors: Konieczny P, Artero R

Abstract
Spinal muscular atrophy is a rare and fatal neuromuscular disorder caused by the loss of alpha motor neurons. The affected individuals have mutated the ubiquitously expressed SMN1 gene resulting in the loss or reduction in the survival motor neuron (SMN) protein levels. However, an almost identical paralog exists in humans: SMN2. Pharmacological activation of SMN2 exon 7 inclusion by small molecules or modified antisense oligonucleotides is a valid approach to treat SMA. Here we describe an in vivo SMN2 minigene reporter system in Drosophila motor neurons that serves as a cost-effective, feasible, and stringent primary screening model for identifying chemicals capable of crossing the conserved Drosophila blood-brain barrier and modulating exon 7 inclusion. The model was used for the screening of 1100 drugs from the Prestwick Chemical Library, resulting in 2.45% hit rate. The most promising candidate drugs were validated in patient-derived fibroblasts where they proved to increase SMN protein levels. Among them, moxifloxacin modulated SMN2 splicing by promoting exon 7 inclusion. The recovery of SMN protein levels was confirmed by increased colocalization of nuclear gems with Cajal Bodies. Thus, a Drosophila-based drug screen allowed the discovery of an FDA-approved small molecule with the potential to become a novel therapy for SMA.

PMID: 31909520 [PubMed - as supplied by publisher]

[Current Therapies for Amyotrophic Lateral Sclerosis in Japan].

Brain Nerve. 2020 Jan;72(1):13-22

Authors: Urushitani M

Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness. Riluzole was the sole drug available for treating ALS until 2015, when edaravone was approved as a new anti-ALS drug. Recent discoveries of the disease-causal genes and proteins, as well as the rapid advancement of induced pluripotent stem (iPS) cell manipulations, drug deliveries, and molecular modifications have provided diverse and promising drug candidates. In particular, antisense-oligonucleotide therapy appears to significantly prevent disease progression when introduced early. Moreover, the in vitro modeling of ALS using patients' own iPS cells enables effective screening of approved drugs. Drug repositioning is a robust short-cut to bedside use in patients with ALS, due to the availability of data for safety concerns. Currently, five investigator-initiated drug trials are underway in Japan. These include trials of hepatocyte growth factor, perampanel, ultra-high-dose methylcobalamin, ropinirole, and bosutinib. This is a review of new ALS drugs that are either currently available or in on-going trials. We additionally review the pathogenic pathways that these drugs target.

PMID: 31907329 [PubMed - in process]

The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.

Int J Mol Sci. 2019 Dec 29;21(1):

Authors: Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV

Abstract
Multidrug resistance caused by the overexpression of the ATP-binding cassette (ABC) proteins in cancer cells remains one of the most difficult challenges faced by drug developers and clinical scientists. The emergence of multidrug-resistant cancers has driven efforts from researchers to develop innovative strategies to improve therapeutic outcomes. Based on the drug repurposing approach, we discovered an additional action of TMP195, a potent and selective inhibitor of class IIa histone deacetylase. We reveal that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs. We demonstrate that TMP195 inhibits the drug transport function, but not the protein expression of ABCB1 and ABCG2. The interaction between TMP195 with these transporters was supported by the TMP195-stimulated ATPase activity of ABCB1 and ABCG2, and by in silico docking analysis of TMP195 binding to the substrate-binding pocket of these transporters. Furthermore, we did not find clear evidence of TMP195 resistance conferred by ABCB1 or ABCG2, suggesting that these transporters are unlikely to play a significant role in the development of resistance to TMP195 in cancer patients.

PMID: 31905792 [PubMed - in process]

Repurposing artemisinin as an anti-mycobacterial agent in synergy with rifampicin.

Tuberculosis (Edinb). 2019 03;115:146-153

Authors: Patel YS, Mistry N, Mehra S

Abstract
The current anti-TB treatment consists of a prolonged multi-drug therapy. Interventional strategies are required to reduce the chemotherapeutic load. In this regard, we have previously identified a synergistic interaction between hydroperoxides and rifampicin. This strategy has been extended here to repurpose a new drug against TB. A hydrophobic antimalarial drug, artemisinin, with an unstable endoperoxide bridge structure, has been investigated as a potential candidate. In combination with rifampicin, artemisinin was found to be synergistic against M. bovis BCG and M. tuberculosis H37Ra. Furthermore, artemisinin was observed to induce peroxides in a time and concentration dependent manner and the levels of the peroxides were significantly higher in cells treated with the drug pair. Coupled with rapid disintegration of the membrane, this enhanced the clearance of the bacterial culture in vitro. On the other hand, formation of the peroxides was significantly reduced in the presence of ascorbic acid, an antioxidant. This translated to a loss of the synergistic effect of the combination, indicating the importance of peroxide formation in the mode of action of artemisinin. Interestingly, artemisinin also had a synergistic interaction with isoniazid, amikacin and ethambutol and an additive interaction with moxifloxacin, other drugs commonly used against TB.

PMID: 30948170 [PubMed - indexed for MEDLINE]

Machine and Deep Learning Approaches for Cancer Drug Repurposing.

Semin Cancer Biol. 2020 Jan 02;:

Authors: Issa NT, Stathias V, Schürer S, Dakshanamurthy S

Abstract
Knowledge of the underpinnings of cancer initiation, progression and metastasis has increased exponentially in recent years. Advanced "omics" coupled with machine learning and artificial intelligence (deep learning) methods have helped elucidate targets and pathways critical to those processes that may be amenable to pharmacologic modulation. However, the current anti-cancer therapeutic armamentarium continues to lag behind. As the cost of developing a new drug remains prohibitively expensive, repurposing of existing approved and investigational drugs is sought after given known safety profiles and reduction in the cost barrier. Notably, successes in oncologic drug repurposing have been infrequent. Computational in-silico strategies have been developed to aid in modeling biological processes to find new disease-relevant targets and discovering novel drug-target and drug-phenotype associations. Machine and deep learning methods have especially enabled leaps in those successes. This review will discuss these methods as they pertain to cancer biology as well as immunomodulation for drug repurposing opportunities in oncologic diseases.

PMID: 31904426 [PubMed - as supplied by publisher]

Chagas Disease Treatment: From New Therapeutic Targets to Drug Discovery and Repositioning.

Curr Med Chem. 2019;26(36):6517-6518

Authors: Miranda MR, Sayé MM

PMID: 31849285 [PubMed - indexed for MEDLINE]

Discovering the in vitro potent inhibitors against Babesia and Theileria parasites by repurposing the Malaria Box: A review.

Vet Parasitol. 2019 Oct;274:108895

Authors: Rizk MA, El-Sayed SAE, El-Khodery S, Yokoyama N, Igarashi I

Abstract
There is an innovative approach to discovering and developing novel potent and safe anti-Babesia and anti-Theileria agents for the control of animal piroplasmosis. Large-scale screening of 400 compounds from a Malaria Box (a treasure trove of 400 diverse compounds with antimalarial activity has been established by Medicines for Malaria Venture) against the in vitro growth of bovine Babesia and equine Babesia and Theileria parasites was performed, and the data were published in a brief with complete dataset from 236 screens of the Malaria Box compounds. Therefore, in this review, we explored and discussed in detail the in vitro inhibitory effects of 400 antimalarial compounds (200 drug-like and 200 probe-like) from the Malaria Box against Babesia (B.) bovis, B. bigemina, B. caballi, and Theileria (T.) equi. Seventeen hits were the most interesting with regard to bovine Babesia parasites, with mean selectivity indices (SIs) greater than 300 and half maximal inhibitory concentration (IC50s) ranging from 50 to 410 nM. The most interesting compounds with regard to equine Babesia and Theileria parasites were MMV020490 and MMV020275, with mean SIs > 258.68 and >251.55, respectively, and IC50s ranging from 76 to 480 nM. Ten novel anti-B. bovis, anti-B. bigemina, anti-T. equi, and anti-B. caballi hits, MMV666093, MMV396794, MMV006706, MMV665941, MMV085203, MMV396693, MMV006787, MMV073843, MMV007092, and MMV665875, with nanomole levels of IC50 were identified. The most interesting hits were MMV396693, MMV073843, MMV666093, and MMV665875, with mean SIs greater than 307.8 and IC50s ranging from 43 to 630 nM for both bovine Babesia and equine Babesia and Theileria parasites. Screening the Malaria Box against the in vitro growth of Babesia and Theileria parasites helped with the discovery of new drugs than those traditionally used, diminazene aceturate and imidocarb dipropionate, and indicated the potential of the Malaria Box in finding new, potent antibabesial drugs.

PMID: 31494399 [PubMed - indexed for MEDLINE]

Repositioning of a mucolytic drug to a selective antibacterial against Vibrio cholerae.

J Microbiol. 2020 Jan;58(1):61-66

Authors: Chung IY, Kim BO, Jang HJ, Cho YH

Abstract
Drug repositioning, the approach to explore existing drugs for use in new therapeutic indications, has emerged as an alternative drug development strategy. In this study, we found that a mucolytic drug, N-acetylcysteine (NAC) showed antibacterial activity against Vibrio cholerae. NAC can provide acid stress that selectively inhibited the growth of V. cholerae among other bacterial pathogens. To address the antibacterial mechanism of NAC against V. cholerae, six acr (acetylcys-teine-resistant) mutants were isolated from 3,118 random transposon insertion clones. The transposon insertion sites of the six mutants were mapped at the five genes. All these mutants did not display NAC resistance under acidic conditions, despite their resistance to NAC under alkaline conditions, indicating that the NAC resistance directed by the acr mutations was independent of the unusual pH-sensitivity of V. cholerae. Furthermore, all these mutants displayed attenuated virulence and reduced biofilm formation, suggesting that the acr genes are required for pathogenesis of V. cholerae. This study validates the relevance of drug repositioning for antibacterials with new modes of action and will provide an insight into a novel antibacterial therapy for V. cholerae infections to minimize side effects and resistance emergence.

PMID: 31898254 [PubMed - in process]

A Drug Repurposing and Protein-Protein Interaction Network Study of Ribosomopathies Using Yeast as a Model System.

OMICS. 2019 Dec 31;:

Authors: Ertekin E, Gencturk E, Kasim M, Ulgen KO

Abstract
Ribosomopathies result in various cancers, neurodegenerative and viral diseases, and other pathologies such as Diamond-Blackfan anemia and Shwachman-Diamond syndrome. Their pathophysiology at a proteome and functional level remains to be determined. Protein networks and highly connected hub proteins for ribosome biogenesis in Saccharomyces cerevisiae offer a potential as a model system to inform future therapeutic innovation in ribosomopathies. In this context, we report a ribosome biogenesis protein-protein interaction network in S. cerevisiae, created with 1772 proteins and 22,185 physical interactions connecting them. Moreover, by network decomposition analysis, we determined the linear pathways between the transcription factors and target proteins with a view to drug repurposing. While considering only the paths containing the three C/D box proteins (Nop56, Nop58, and Nop1), the most frequently encountered proteins were Aft1, Htz1, Ssa1, Ssb1, Ssb2, Gcn5, Cka1, Tef1, Nop1, Cdc28, Act1, Krr1, Rpl8B, and Tor1, which were then identified as potential drug targets. For drug repurposing, these candidate proteins were further searched in the DrugBank to find other diseases associated with them, as well as the drugs used to treat these diseases. To support the computational results, an experimental study was conducted using in-house manufactured microfluidic bioreactor platform, while the effect of the drug temsirolimus, Tor1 inhibitor, on yeast cells was investigated by following Nop56 protein expression. In conclusion, these results inform the ways in which ribosomopathies and associated common complex human diseases materialize and how drug repurposing might accelerate therapeutic innovation through bioinformatic studies of yeast.

PMID: 31895625 [PubMed - as supplied by publisher]

Building the drug-GO function network to screen significant candidate drugs for myasthenia gravis.

PLoS One. 2019;14(4):e0214857

Authors: Li S, Cao Y, Li L, Zhang H, Lu X, Bo C, Kong X, Liu Z, Chen L, Liu P, Jiao Y, Wang J, Ning S, Wang L

Abstract
Myasthenia gravis (MG) is an autoimmune disease. In recent years, considerable evidence has indicated that Gene Ontology (GO) functions, especially GO-biological processes, have important effects on the mechanisms and treatments of different diseases. However, the roles of GO functions in the pathogenesis and treatment of MG have not been well studied. This study aimed to uncover the potential important roles of risk-related GO functions and to screen significant candidate drugs related to GO functions for MG. Based on MG risk genes, 238 risk GO functions and 42 drugs were identified. Through constructing a GO function network, we discovered that positive regulation of NF-kappaB transcription factor activity (GO:0051092) may be one of the most important GO functions in the mechanism of MG. Furthermore, we built a drug-GO function network to help evaluate the latent relationship between drugs and GO functions. According to the drug-GO function network, 5 candidate drugs showing promise for treating MG were identified. Indeed, 2 out of 5 candidate drugs have been investigated to treat MG. Through functional enrichment analysis, we found that the mechanisms between 5 candidate drugs and associated GO functions may involve two vital pathways, specifically hsa05332 (graft-versus-host disease) and hsa04940 (type I diabetes mellitus). More interestingly, most of the processes in these two pathways were consistent. Our study will not only reveal a new perspective on the mechanisms and novel treatment strategies of MG, but also will provide strong support for research on GO functions.

PMID: 30947317 [PubMed - indexed for MEDLINE]

Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder: The first-reported Latin-American case with response to doxycycline.

Clin Case Rep. 2019 Dec;7(12):2405-2409

Authors: Escanilla C, Guavita Falla PM, Cevallos C, Ávalos Jobet N, Bobadilla Bruneau F

Abstract
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder is a provisional entity according to the last WHO-EORTC classification. The treatment of choice has not yet been defined. Local therapies have been used with variable response. Doxycycline as a main treatment option is a potential low-cost and effective alternative for this disorder.

PMID: 31893069 [PubMed]

The evolving therapeutic landscape of genetic skeletal disorders.

Orphanet J Rare Dis. 2019 Dec 30;14(1):300

Authors: Sabir AH, Cole T

Abstract
BACKGROUND: Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials.
METHODS: A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review.
RESULTS: Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP.
DISCUSSION: It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.

PMID: 31888683 [PubMed - in process]

Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology.

Semin Cancer Biol. 2019 Dec 26;:

Authors: Efferth T, Oesch F

Abstract
Drug repurposing (or repositioning) is an emerging concept to use old drugs for new treatment indications. Phytochemicals isolated from medicinal plants have been largely neglected in this context, although their pharmacological activities have been well investigated in the past, and they may have considerable potentials for repositioning. A grand number of plant alkaloids inhibit syngeneic or xenograft tumor growth in vivo. Molecular modes of action in cancer cells include induction of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, cellular differentiation, and inhibition of invasion and metastasis. Numerous underlying signaling processes are affected by plant alkaloids. Furthermore, plant alkaloids suppress carcinogenesis, indicating chemopreventive properties. Some plant alkaloids reveal toxicities such as hepato-, nephro- or genotoxicity, which disqualifies them for repositioning purposes. Others even protect from hepatotoxicity or cardiotoxicity of xenobiotics and established anticancer drugs. The present survey of the published literature clearly demonstrates that plant alkaloids have the potential for repositioning in cancer therapy. Exploitation of the chemical diversity of natural alkaloids may enrich the candidate pool of compounds for cancer chemotherapy and -prevention. Their further preclinical and clinical development should follow the same stringent rules as for any other synthetic drug as well. Prospective randomized, placebo-controlled clinical phase I and II trials should be initiated to unravel the full potential of plant alkaloids for drug repositioning.

PMID: 31883912 [PubMed - as supplied by publisher]

Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections.

Sci Rep. 2019 01 09;9(1):17

Authors: Marrugal-Lorenzo JA, Serna-Gallego A, Berastegui-Cabrera J, Pachón J, Sánchez-Céspedes J

Abstract
The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia.

PMID: 30626902 [PubMed - indexed for MEDLINE]

Old drug repositioning and new drug discovery through similarity learning from drug-target joint feature spaces.

BMC Bioinformatics. 2019 Dec 27;20(Suppl 23):605

Authors: Zheng Y, Peng H, Zhang X, Zhao Z, Gao X, Li J

Abstract
BACKGROUND: Detection of new drug-target interactions by computational algorithms is of crucial value to both old drug repositioning and new drug discovery. Existing machine-learning methods rely only on experimentally validated drug-target interactions (i.e., positive samples) for the predictions. Their performance is severely impeded by the lack of reliable negative samples.
RESULTS: We propose a method to construct highly-reliable negative samples for drug target prediction by a pairwise drug-target similarity measurement and OCSVM with a high-recall constraint. On one hand, we measure the pairwise similarity between every two drug-target interactions by combining the chemical similarity between their drugs and the Gene Ontology-based similarity between their targets. Then we calculate the accumulative similarity with all known drug-target interactions for each unobserved drug-target interaction. On the other hand, we obtain the signed distance from OCSVM learned from the known interactions with high recall (≥0.95) for each unobserved drug-target interaction. After normalizing all accumulative similarities and signed distances to the range [0,1], we compute the score for each unobserved drug-target interaction via averaging its accumulative similarity and signed distance. Unobserved interactions with lower scores are preferentially served as reliable negative samples for the classification algorithms. The performance of the proposed method is evaluated on the interaction data between 1094 drugs and 1556 target proteins. Extensive comparison experiments using four classical classifiers and one domain predictive method demonstrate the superior performance of the proposed method. A better decision boundary has been learned from the constructed reliable negative samples.
CONCLUSIONS: Proper construction of highly-reliable negative samples can help the classification models learn a clear decision boundary which contributes to the performance improvement.

PMID: 31881829 [PubMed - in process]

Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles.

EBioMedicine. 2019 Dec 23;:102585

Authors: Malas TB, Leonhard WN, Bange H, Granchi Z, Hettne KM, Van Westen GJP, Price LS, 't Hoen PAC, Peters DJM

Abstract
BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Tolvaptan, the only drug approved for ADPKD treatment, results in serious side-effects, warranting the need for novel drugs.
METHODS: In this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. We followed an integrative computational approach using a combination of gene expression profiling, bioinformatics and cheminformatics data.
FINDINGS: We identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinically-approved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone. Further testing the efficacy of six candidate drugs for inhibition of cyst swelling using a human 3D-cyst assay, revealed that three of the six had cyst-growth reducing effects with limited toxicity.
INTERPRETATION: Our data further establishes drug repurposing as a robust drug discovery method, with three promising drug candidates identified for ADPKD treatment (Meclofenamic Acid, Gamolenic Acid and Birinapant). Our strategy that combines multiple-omics data, can be extended for ADPKD and other diseases in the future.
FUNDING: European Union's Seventh Framework Program, Dutch Technology Foundation Stichting Technische Wetenschappen and the Dutch Kidney Foundation.

PMID: 31879244 [PubMed - as supplied by publisher]

The antifungal isavuconazole inhibits the entry of lassa virus by targeting the stable signal peptide-GP2 subunit interface of lassa virus glycoprotein.

Antiviral Res. 2019 Dec 23;:104701

Authors: Zhang X, Tang K, Guo Y

Abstract
Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever in humans, and the limited therapeutic treatment for Lassa fever poses significant threat to public health in West Africa. Using an HIV based pseudovirus platform, we identified isavuconazole, a triazole antifungal for systemic use, as a LASV entry inhibitor with an EC50 of 1.2 μM. Isavuconazole inhibits Lassa virus entry by blocking the pH dependent viral fusion mediated by the Lassa virus surface glycoprotein. Fragment replacement mutational study indicated that isavuconazole targets the stable signal peptide (SSP)-membrane fusion subunit (GP2) interface of Lassa glycoprotein. Further mutational study of the SSP-GP2 region of LASV glycoprotein revealed that S27 in the N-terminal transmembrane region of SSP and V431, F434 and V435 in the transmembrane domain of GP2 affect anti-LASV activity of isavuconazole. Isavuconazole also displays antiviral activity to five New World (NW) mammarenaviruses that cause hemorrhagic fever. This study facilitates the potential repurposing of isavuconazole for therapeutic intervention against human-pathogenic arenaviruses, and provides the basis for further structural optimization of arenavirus fusion inhibitors based on the predicted structural characteristics of the unique SSP-GP2 interface.

PMID: 31877348 [PubMed - as supplied by publisher]

Drug Repurposing for Cancer Therapy, Easier Said Than Done.

Semin Cancer Biol. 2019 Dec 23;:

Authors: Gonzalez-Fierro A, Dueñas-González A

Abstract
Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

PMID: 31877340 [PubMed - as supplied by publisher]

Repurposing existing medications in oncology and their potential role in oral cancer.

Oral Dis. 2019 01;25(1):6-9

Authors: Basile JR, Czerninski R

PMID: 29575546 [PubMed - indexed for MEDLINE]

Drug repositioning based on individual bi-random walks on a heterogeneous network.

BMC Bioinformatics. 2019 Dec 24;20(Suppl 15):547

Authors: Wang Y, Guo M, Ren Y, Jia L, Yu G

Abstract
BACKGROUND: Traditional drug research and development is high cost, time-consuming and risky. Computationally identifying new indications for existing drugs, referred as drug repositioning, greatly reduces the cost and attracts ever-increasing research interests. Many network-based methods have been proposed for drug repositioning and most of them apply random walk on a heterogeneous network consisted with disease and drug nodes. However, these methods generally adopt the same walk-length for all nodes, and ignore the different contributions of different nodes.
RESULTS: In this study, we propose a drug repositioning approach based on individual bi-random walks (DR-IBRW) on the heterogeneous network. DR-IBRW firstly quantifies the individual work-length of random walks for each node based on the network topology and knowledge that similar drugs tend to be associated with similar diseases. To account for the inner structural difference of the heterogeneous network, it performs bi-random walks with the quantified walk-lengths, and thus to identify new indications for approved drugs. Empirical study on public datasets shows that DR-IBRW achieves a much better drug repositioning performance than other related competitive methods.
CONCLUSIONS: Using individual random walk-lengths for different nodes of heterogeneous network indeed boosts the repositioning performance. DR-IBRW can be easily generalized to prioritize links between nodes of a network.

PMID: 31874623 [PubMed - in process]