Searching drugs for Chagas disease, leishmaniasis and schistosomiasis: a brief review.

Int J Antimicrob Agents. 2020 Jan 24;:105906

Authors: Santos SS, de Araújo RV, Giarolla J, Seoud OE, Ferreira EI

Abstract
Chagas disease, leishmaniasis and schistosomiasis are neglected diseases, also known as diseases for neglected poor population, and have been a great challenge for many countries in the world. Despite the huge number of infected people, those diseases do not raise interest from pharmaceutical industries because, generally, the revenue is low. Most of the research on those diseases has been developed in academic institutions. The chemotherapeutic armamentarium for those diseases is, generally, scarce, not completely efficient and secure and better drugs are needed. Using medicinal chemistry and computational approaches, researchers have found some promising compounds, most of them synthetic, but also from natural sources or even semi-synthetic, which could be drug candidates. On the other hand, drug repurposing or repositioning has been greatly stimulated, considering its advantages, especially for neglected diseases. Examples of some compounds, as well as details of their design/discovery and activity have been given in this review.

PMID: 31987883 [PubMed - as supplied by publisher]

Inferring new relations between medical entities using literature curated term co-occurrences.

JAMIA Open. 2019 Oct;2(3):378-385

Authors: Spiro A, Fernández García J, Yanover C

Abstract
Objectives: Identifying new relations between medical entities, such as drugs, diseases, and side effects, is typically a resource-intensive task, involving experimentation and clinical trials. The increased availability of related data and curated knowledge enables a computational approach to this task, notably by training models to predict likely relations. Such models rely on meaningful representations of the medical entities being studied. We propose a generic features vector representation that leverages co-occurrences of medical terms, linked with PubMed citations.
Materials and Methods: We demonstrate the usefulness of the proposed representation by inferring two types of relations: a drug causes a side effect and a drug treats an indication. To predict these relations and assess their effectiveness, we applied 2 modeling approaches: multi-task modeling using neural networks and single-task modeling based on gradient boosting machines and logistic regression.
Results: These trained models, which predict either side effects or indications, obtained significantly better results than baseline models that use a single direct co-occurrence feature. The results demonstrate the advantage of a comprehensive representation.
Discussion: Selecting the appropriate representation has an immense impact on the predictive performance of machine learning models. Our proposed representation is powerful, as it spans multiple medical domains and can be used to predict a wide range of relation types.
Conclusion: The discovery of new relations between various medical entities can be translated into meaningful insights, for example, related to drug development or disease understanding. Our representation of medical entities can be used to train models that predict such relations, thus accelerating healthcare-related discoveries.

PMID: 31984370 [PubMed]

A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-κB Activation.

Mol Ther Nucleic Acids. 2020 Jan 10;19:890-904

Authors: Zhang Y, Mao X, Chen W, Guo X, Yu L, Jiang F, Wang X, Li W, Guo Q, Li T, Lin N

Abstract
Drug repositioning offers new clinical applications for existing drugs with shorter approval processes and lower costs and risks than de novo experimental drug development. The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved anti-fibrosis herbal formula in China. Whether FBRP could be used to treat hepatocellular carcinoma (HCC) remains unclear. Herein, a total of 161 FBRP candidate targets against HCC were identified according to the topological importance in the "hepatic fibrosis-cirrhosis-cancer axis-related gene-FBRP putative target" network, and mostly enriched in phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear factor κB (NF-κB) signaling. Experimentally, FBRP inhibited liver fibrosis and prevented the development of neoplastic lesions at the early stages of hepatocarcinogenesis in a diethylnitrosamine-induced rat HCC model. FBRP inhibited tumor cell proliferation, induced tumor-specific cell death, and suppressed tumor progression in HCC rats while preventing the activation of PI3K, AKT and IKΚB proteins, reducing the nuclear accumulation of NFΚB1 protein, and decreasing the downstream expression of proteins. Consistently, FBRP suppressed HCC cell proliferation and induced cell cycle arrest in vitro. Co-treatment of FBRP with PI3K inhibitor exhibited an additive inhibitory effect on PI3K/AKT/NF-κB activation. Collectively, our data showed the potentials of FBRP in hepatic fibrosis microenvironment regulation and tumor prevention, suggesting that FBRP may be a promising candidate drug for reduction of fibrogenesis and prevention of HCC.

PMID: 31982775 [PubMed - as supplied by publisher]

Next-generation drug repurposing using human genetics and network biology.

Curr Opin Pharmacol. 2020 Jan 22;:

Authors: Nabirotchkin S, Peluffo AE, Rinaudo P, Yu J, Hajj R, Cohen D

Abstract
Drug repurposing has attracted increased attention, especially in the context of drug discovery rates that remain too low despite a recent wave of approvals for biological therapeutics (e.g. gene therapy). These new biological entities-based treatments have high costs that are difficult to justify for small markets that include rare diseases. Drug repurposing, involving the identification of single or combinations of existing drugs based on human genetics data and network biology approaches represents a next-generation approach that has the potential to increase the speed of drug discovery at a lower cost. This Pharmacological Perspective reviews progress and perspectives in combining human genetics, especially genome-wide association studies, with network biology to drive drug repurposing for rare and common diseases with monogenic or polygenic etiologies. Also, highlighted here are important features of this next generation approach to drug repurposing, which can be combined with machine learning methods to meet the challenges of personalized medicine.

PMID: 31982325 [PubMed - as supplied by publisher]

Informatics-guided drug repurposing for Autosomal Dominant Polycystic Kidney Disease (ADPKD).

EBioMedicine. 2020 Jan 22;52:102628

Authors: Kiseleva AA, Golemis EA

PMID: 31981981 [PubMed - as supplied by publisher]

The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients.

Psychol Med. 2020 Jan 24;:1-9

Authors: Shaw RJ, Mackay D, Pell JP, Padmanabhan S, Bailey DS, Smith DJ

Abstract
BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD).
METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.
RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.
CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

PMID: 31973782 [PubMed - as supplied by publisher]

Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug.

Arthritis Res Ther. 2020 Jan 23;22(1):16

Authors: Samarpita S, Kim JY, Rasool MK, Kim KS

Abstract
BACKGROUND: Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis.
METHODS: The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model.
RESULTS: TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR.
CONCLUSIONS: Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.

PMID: 31973752 [PubMed - in process]

Corrigendum to "Evaluation of imidazole and its derivative against Newcastle disease virus infection in chicken: A drug repurposing approach" [Virus Res. (2019) 260 114-122].

Virus Res. 2020 Jan 20;278:197859

Authors: Das M, Baro S, Kumar S

PMID: 31972472 [PubMed - as supplied by publisher]

Network-based Prediction of Drug-Target Interactions using an Arbitrary-Order Proximity Embedded Deep Forest.

Bioinformatics. 2020 Jan 23;:

Authors: Zeng X, Zhu S, Hou Y, Zhang P, Li L, Li J, Huang LF, Lewis SJ, Nussinov R, Cheng F

Abstract
MOTIVATION: Systematic identification of molecular targets among known drugs plays an essential role in drug repurposing and understanding of their unexpected side effects. Computational approaches for prediction of drug-target interactions (DTIs) are highly desired in comparison to traditional experimental assays. Furthermore, recent advances of multi-omics technologies and systems biology approaches have generated large-scale heterogeneous, biological networks, which offer unexpected opportunities for network-based identification of new molecular targets among known drugs.
RESULTS: In this study, we present a network-based computational framework, termed AOPEDF, an Arbitrary-Order Proximity Embedded Deep Forest approach, for prediction of DTIs. AOPEDF learns a low-dimensional vector representation of features that preserve arbitrary-order proximity from a highly integrated, heterogeneous biological network connecting drugs, targets (proteins), and diseases. In total, we construct a heterogeneous network by uniquely integrating 15 networks covering chemical, genomic, phenotypic, and network profiles among drugs, proteins/targets, and diseases. Then, we build a cascade deep forest classifier to infer new DTIs. Via systematic performance evaluation, AOPEDF achieves high accuracy in identifying molecular targets among known drugs on two external validation sets collected from DrugCentral (area under receiver operating characteristic curve [AUROC] = 0.868) and ChEMBL (AUROC = 0.768) databases, outperforming several state-of-the-art methods. In a case study, we showcase that multiple molecular targets predicted by AOPEDF are associated with mechanism-of-action of substance abuse disorder for several marketed drugs (such as aripiprazole, risperidone, and haloperidol).
AVAILABILITY: Source code and data can be downloaded from https://github.com/ChengF-Lab/AOPEDF.
SUPPLEMENTARY INFORMATION: Supplementary data are available online at Bioinformatics.

PMID: 31971579 [PubMed - as supplied by publisher]

Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition.

Mol Cancer Res. 2019 01;17(1):42-53

Authors: Mattoo AR, Joun A, Jessup JM

Abstract
MCL-1, a member of the antiapoptotic BCL-2 family, is a prosurvival protein with an essential DNA repair function. This study aims to test whether inhibition of protein synthesis by mTOR complex (mTORC) inhibitors depletes MCL-1, suppresses homologous recombination (HR) repair, and sensitizes cancer cells to PARP inhibitors. Treatment with everolimus decreases MCL-1 in colorectal carcinomas and small cell lung cancer (SCLC) cells but not glioblastoma multiforme (GBM) cells with a PTEN mutational background. However, AZD2014, a dual mTORC inhibitor, depletes MCL-1 in GBMs. Further, we show that everolimus decreases 4EBP1 phosphorylation only in colorectal carcinoma, whereas AZD2014 decreases 4EBP1 phosphorylation in both colorectal carcinoma and GBM cells. Combination therapy using everolimus or AZD2014 with olaparib inhibits the growth of clone A and U87-MG xenografts in in vivo and decreases clonogenic survival in in vitro compared with monotherapy. Reintroduction of MCL-1 rescues the survival of cancer cells in response to combination of everolimus or AZD2014 with olaparib. Treatment of cells with mTORC inhibitors and olaparib increases γ-H2AX and 53BP1 foci, decreases BRCA1, RPA, and Rad51 foci, impairs phosphorylation of ATR/Chk1 kinases, and induces necroptosis. In summary, mTORC inhibitors deplete MCL-1 to suppress HR repair and increase sensitivity to olaparib both in in vitro and in xenografts. IMPLICATIONS: Targeting the DNA repair activity of MCL-1 in in vivo for cancer therapy has not been tested. This study demonstrates that depleting MCL-1 sensitizes cancer cells to PARP inhibitors besides eliciting necroptosis, which could stimulate antitumor immunity to improve the therapeutic intervention of cancers.

PMID: 30201826 [PubMed - indexed for MEDLINE]

Pharmacological enrichment of polygenic risk for precision medicine in complex disorders.

Sci Rep. 2020 Jan 21;10(1):879

Authors: Reay WR, Atkins JR, Carr VJ, Green MJ, Cairns MJ

Abstract
Individuals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an individual's common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for individual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, antioxidants, insulin modulating agents, and cholinergic drugs. Interestingly, elevated PES was also observed in individuals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this gene-set orientated approach could integrate an individual's common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.

PMID: 31964963 [PubMed - in process]

Lead optimisation of dehydroemetine for repositioned use in malaria.

Antimicrob Agents Chemother. 2020 Jan 21;:

Authors: Panwar P, Burusco KK, Abubaker M, Matthews H, Gutnov A, Fernández-Álvaro E, Bryce RA, Wilkinson J, Nirmalan N

Abstract
Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action.

PMID: 31964796 [PubMed - as supplied by publisher]

An update on derivatisation and repurposing of clinical nitrofuran drugs.

Eur J Pharm Sci. 2019 Dec 01;140:105092

Authors: Zuma NH, Aucamp J, N'Da DD

Abstract
5-nitrofurans (NFs) have been in clinical use for over 60 years. These affordable drugs are used for the treatment of a broad spectrum of diseases ranging from urinary tract infections to cancer. The anti-pathogenic effect of clinical NFs occurs following a step-wise process involving activation by azoreduction, followed by nitroreduction catalysed by azoreductases and nitroreductases (NTRs), respectively. Azoreduction yields stable metabolites that have the ability to covalently bind to cellular proteins. Nitroreduction, on the other hand, occurs by type I or II reduction of the nitro group in the presence of parasitic NADPH-cytochrome P450 reductases. Type I NTRs catalyse, under anaerobic conditions, the reduction of NFs to produce anti-pathogenic hydroxylamine. Under aerobic conditions, nitroreduction catalysed by type II NTRs produces reactive oxygen and nitrogen species (ROS/RNS), causing oxidative stress to pathogens and ultimate death. This multi-activity nature of NFs thus allows the repurposing of these drugs from agricultural chemicals and basic antibiotics to efficient therapies against human life-threatening diseases. Cases of NF resistance in pathogens are also limited likely due to this multi-activity, as well as effectivity under both aerobic and anaerobic conditions. However, multi-activity of these drugs can also infer toxicity. Molecular derivatisation is an effective strategy to improve efficacy, lower toxicity, diversify activity and address pathogen resistance associated with the use of these drugs.

PMID: 31634556 [PubMed - indexed for MEDLINE]

Anti-inflammatory Strategies for Schizophrenia: A Review of Evidence for Therapeutic Applications and Drug Repurposing.

Clin Psychopharmacol Neurosci. 2020 Feb 29;18(1):10-24

Authors: Hong J, Bang M

Abstract
Schizophrenia is a debilitating psychiatric disorder with a substantial socioeconomic and humanistic burden. Currently available treatment strategies mostly rely on antipsychotic drugs, which block dopaminergic effects in the mesolimbic pathway of the brain. Although antipsychotic drugs help relieve psychotic symptoms, a definitive cure for schizophrenia has yet to be achieved. Recent advances in neuroinflammation research suggest that proinflammatory processes in the brain could cause alterations in neurobehavioral development and increase vulnerability to schizophrenia. With a growing need for novel strategies in the treatment of schizophrenia, it would be meaningful to review the current evidence supporting the therapeutic potential of anti-inflammatory strategies. This review details the key findings of clinical trials that investigate the efficacy of anti-inflammatory agents as adjuvants to antipsychotic treatment. We further discuss the possibilities of repurposing anti-inflammatory agents and developing novel strategies for the treatment of schizophrenia.

PMID: 31958901 [PubMed]

Multifunctional compounds Lithium Chloride and Methylene Blue attenuate the negative effects of diisopropylfluorophosphate on axonal transport in rat cortical neurons.

Toxicology. 2020 Jan 18;:152379

Authors: Naughton SX, Beck WD, Wei Z, Wu G, Terry AV

Abstract
Organophosphates (OPs) are valuable as pesticides in agriculture and for controlling deadly vector-borne illnesses; however, they are highly toxic and associated with many deleterious health effects in humans including long-term neurological impairments. Antidotal treatment regimens are available to combat the symptoms of acute OP toxicity, which result from the irreversible inhibition of acetylcholinesterase (AChE). However, there are no established treatments for the long-term neurological consequences of OP exposure. In addition to AChE, OPs can negatively affect multiple protein targets as well as biological processes such as axonal transport. Given the fundamental nature of axonal transport to neuronal health, we rationalized that this process might serve as a general focus area for novel therapeutic strategies against OP toxicity. In the studies described here, we employed a multi-target, phenotypic screening, and drug repurposing strategy for the evaluations of potential novel OP-treatments using a primary neuronal culture model and time-lapse live imaging microscopy. Two multi-target compounds, lithium chloride (LiCl) and methylene blue (MB), which are FDA-approved for other indications, were evaluated for their ability to prevent the negative effects of the OP, diisopropylfluorophosphate (DFP) on axonal transport. The results indicated that both LiCl and MB prevented DFP-induced impairments in anterograde and retrograde axonal transport velocities in a concentration dependent manner. While in vivo studies will be required to confirm our in vitro findings, these experiments support the potential of LiCl and MB as repurposed drugs for the treatment of the long-term neurological deficits associated with OP exposure (currently an unmet medical need).

PMID: 31962143 [PubMed - as supplied by publisher]

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069.

PLoS Negl Trop Dis. 2020 Jan 21;14(1):e0007481

Authors: Sayé M, Gauna L, Valera-Vera E, Reigada C, Miranda MR, Pereira CA

Abstract
BACKGROUND: Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069.
METHODOLOGY/PRINCIPAL FINDINGS: CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and DM28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain.
CONCLUSIONS/SIGNIFICANCE: Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.

PMID: 31961864 [PubMed - as supplied by publisher]

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor.

Cancer Lett. 2019 05 01;449:45-55

Authors: Ahmed K, Koval A, Xu J, Bodmer A, Katanaev VL

Abstract
Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro. In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and well-characterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments.

PMID: 30771433 [PubMed - indexed for MEDLINE]

Therapeutic Potentials and Mechanisms of Artemisinin and its Derivatives for Tumorigenesis and Metastasis.

Anticancer Agents Med Chem. 2020 Jan 19;:

Authors: Li Y, Zhou X, Liu J, Yuan X, He Q

Abstract
BACKGROUND: Tumor recurrence and metastasis are still leading causes of cancer mortality worldwide. The influence of traditional treatment strategies against metastatic tumor may still be limited. To search for novel and powerful agents against tumors become a major research focus. In this study, Artemisinin (ARM), a natural compound isolated from herbs, Artemisia annua L., proceeding from drug repurposing methods, attracts more attention due to its good efficacy and tolerance in antimalarial practices, as well as newly confirmed anticancer activity.
METHODS: We have searched and reviewed the literatures about ARM and its derivatives (ARMs) for cancer using keywords 'artemisinin' until May 2019.
RESULTS: In preclinical studies, ARMs can induce cell cycle arrest and cell death by apoptosis etc., to inhibit the progression of tumors, and suppress EMT and angiogenesis to inhibit the metastasis of tumors. Notably, the complex relationships of ARMs and autophagy is worth exploring. Inspired by the limitations of its antimalarial applications and the mechanical studies of artemisinin and cancer, people are also committed to develop safer and more potent ARM-based modified compounds (ARMs) or combination therapy, such as artemisinin dimers/trimers, artemisinin-derived hybrids. Some clinical trials support artemisinins as promising candidates for cancer therapy.
CONCLUSION: ARMs show potent therapeutic potentials against carcinoma including metastatic tumors. Novel compounds derived from artemisinin and relevant combination therapies are supposed to be promising treatment strategies for tumors, as the important future research directions.

PMID: 31958040 [PubMed - as supplied by publisher]

Drug repositioning in cancer: the current situation in Japan.

Cancer Sci. 2020 Jan 19;:

Authors: Masuda T, Tsuruda Y, Matsumoto Y, Uchida H, Nakayama KI, Mimori K

Abstract
Cancer is a leading cause of mortality worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in recent years. DR now has become a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics, and bioinformatics has accelerated the pace of activity-based, literature-based, and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

PMID: 31957175 [PubMed - as supplied by publisher]

A Review of Recent Developments and Progress in Computational Drug Repositioning.

Curr Pharm Des. 2020 Jan 16;:

Authors: Shi W, Chen X, Deng L

Abstract
Computational drug repositioning is an efficient approach towards discovering new indications for existing drugs. In recent years, with the accumulation of online health-related information and the extensive use of biomedical databases, computational drug repositioning approaches have achieved significant progress in drug discovery. In this review, we summarize recent advancements in drug repositioning. Firstly, we detailed demonstrate available data source information which is conducive to identifying novel indications. Furthermore, we provide a summary of commonly used computing approaches. For each method, we briefly describe techniques, case studies, and evaluation criteria. Finally, we discuss the limitations of existing computing approaches.

PMID: 31951162 [PubMed - as supplied by publisher]