Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.

Sci Rep. 2017 Apr 06;7(1):682

Authors: Wang S, Wang L, Zhou Z, Deng Q, Li L, Zhang M, Liu L, Li Y

Abstract
Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.

PMID: 28386133 [PubMed - in process]

The challenge of the new tuberculosis drugs.

Presse Med. 2017 Mar;46(2 Pt 2):e41-e51

Authors: Tiberi S, Buchanan R, Caminero JA, Centis R, Arbex MA, Salazar M, Potter J, Migliori GB

Abstract
Tuberculosis (TB) continues to cause more deaths worldwide than any other single infectious disease. Even though tuberculosis appears to be decreasing in incidence globally for some time, the proportion of drug resistance is increasing, contributing to greater complexity, morbidity and mortality as well as cost. Since the advent of rifampicin in the 1960s, and the implementation of standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have been changed the first line regimen. This regimen is effective however it is pill burden, and duration has not received investment and innovation. Drug-resistant regimens are long and frequently poorly tolerated due to significant toxicity. This review is an update on what is new in the treatment of drug-susceptible and drug-resistant tuberculosis, new TB drugs currently being used and studied in clinical trials are also mentioned. Fortunately, there have been many significant advances in this field in recent years. The horizon is changing with the new WHO shorter multidrug-resistant tuberculosis regimens and with the increasing availability of new or repurposed drugs like bedaquiline, delamanid, clofazimine and linezolid. These drugs pose new challenges relating to their rational use to prevent selection of resistant strains of Mycobacterium tuberculosis even before a new regimen has been studied. The availability of these new drugs is offering hope and new possibilities for saving patients who had few or no treatment options. Their use and combination into effective regimens need to be studied; trials are in progress. It is hoped that soon we will be able to treat sensitive and drug-resistant cases with a universal regimen, this would revolutionise treatment and take us another step closer towards elimination.

PMID: 28256383 [PubMed - indexed for MEDLINE]

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

Assay Drug Dev Technol. 2017 Apr 05;:

Authors: Pulley JM, Shirey-Rice JK, Lavieri RR, Jerome RN, Zaleski NM, Aronoff DM, Bastarache L, Niu X, Holroyd KJ, Roden DM, Skaar EP, Niswender CM, Marnett LJ, Lindsley CW, Ekstrom LB, Bentley AR, Bernard GR, Hong CC, Denny JC

Abstract
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.

PMID: 28379727 [PubMed - as supplied by publisher]

Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor cells.

Biochem Pharmacol. 2017 Apr 01;:

Authors: Bonvicini F, Bua G, Conti I, Manaresi E, Gallinella G

Abstract
Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis and severe complications mainly in subjects with underlying hematological disorders or with immune system deficits. Currently, there are no specific antiviral drugs for B19V treatment, but identification of compounds inhibiting B19V replication can be pursued by a drug repositioning strategy. In this frame, the present study investigates the activity of hydroxyurea (HU), the only disease-modifying therapy approved for sickle cell disease (SCD), towards B19V replication in the two relevant cellular systems, the UT7/EpoS1 cell line and EPCs. Results demonstrate that HU inhibits B19V replication with EC50 values of 96.2 µM and 147.1 µM in UT7/EpoS1 and EPCs, respectively, providing experimental evidence of the antiviral activity of HU towards B19V replication, and confirming the efficacy of a drug discovery process by drug repositioning strategy. The antiviral activity occurs in vitro at concentrations lower than those affecting cellular DNA replication and viability, and at levels measured in plasma samples of SCD patients undergoing HU therapy. HU might determine a dual beneficial effect on SCD patients, not only for the treatment of the disease but also towards a virus responsible for severe complications.

PMID: 28377277 [PubMed - as supplied by publisher]

Make better, safer biomaterials.

Nature. 2016 12 14;540(7633):335-337

Authors: Peppas NA, Khademhosseini A

PMID: 27974790 [PubMed - indexed for MEDLINE]

Suppressive effects of dabrafenib on endothelial protein C receptor shedding.

Arch Pharm Res. 2017 Feb;40(2):282-290

Authors: Ku SK, Kim J, Kim SC, Bae JS

Abstract
Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. However, little is known about the effects of DAB on EPCR shedding. We investigated this issue by monitoring the effects of DAB on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Data demonstrate that DAB induced potent inhibition of PMA-, TNF-α-, IL-1β- (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. DAB also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be molecular targets of DAB. These results demonstrate the potential of DAB as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding.

PMID: 27909955 [PubMed - indexed for MEDLINE]

Pharma Perspective on Drug Repurposing.

Br J Pharmacol. 2017 Mar 29;:

Authors: Cha Y, Erez T, Reynolds IJ, Kumar D, Ross J, Koytiger G, Kusko R, Zeskind B, Risso S, Kagan E, Papapetropoulos S, Grossman I, Laifenfeld D

Abstract
Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug R&D, combined with the advent of big-data repositories and associated analytics has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in-silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecule data, appropriate analytical expertise to enable robust insights, expertise and experimental set up for validation, and clinical development know-how. In this review we describe some of the main approaches to systematic repurposing, discuss the various players in this field and the need for strategic collaborations to increase likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug-development strategy pursued by pharmaceutical companies.

PMID: 28369768 [PubMed - as supplied by publisher]

An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method.

Eur J Med Chem. 2017 Mar 28;132:249-261

Authors: Lara-Ramirez EE, López-Cedillo JC, Nogueda-Torres B, Kashif M, Garcia-Perez C, Bocanegra-Garcia V, Agusti R, Uhrig ML, Rivera G

Abstract
Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion-exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti-hypertensive, and antibiotic properties showed better trypanocidal effects (LC50 range = 4.5-25.8 μg/mL) than the reference drugs, nifurtimox and benznidazole (LC50 range = 36.1-46.8 μg/mL) in both strains in the in vitro model. The anti-inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors.

PMID: 28364659 [PubMed - as supplied by publisher]

Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke.

Neurochem Res. 2017 Mar 31;:

Authors: Staal RG, Weinstein JR, Nattini M, Cajina M, Chandresana G, Möller T

Abstract
Stroke is the leading cause of serious long-term disability and the fifth leading cause of death in the United States. Treatment options for stroke are few in number and limited in efficacy. Neuroinflammation mediated by microglia and infiltrating peripheral immune cells is a major component of stroke pathophysiology. Interfering with the inflammation cascade after stroke holds the promise to modulate stroke outcome. The calcium activated potassium channel KCa3.1 is expressed selectively in the injured CNS by microglia. KCa3.1 function has been implicated in pro-inflammatory activation of microglia and there is recent literature suggesting that this channel is important in the pathophysiology of ischemia/reperfusion (stroke) related brain injury. Here we describe the potential of repurposing Senicapoc, a KCa3.1 inhibitor, to intervene in the inflammation cascade that follows ischemia/reperfusion.

PMID: 28364331 [PubMed - as supplied by publisher]

Laying in silico pipelines for drug repositioning: a paradigm in ensemble analysis for neurodegenerative diseases.

Drug Discov Today. 2017 Mar 28;:

Authors: Dovrolis N, Kolios G, Spyrou G, Maroulakou I

Abstract
When faced with time- and money-consuming problems, new practices in pharmaceutical R&D arose when trying to alleviate them. Drug repositioning has great promise and when combined with today's computational power and intelligence it becomes more precise and potent. This work showcases current approaches of creating a computational pipeline for drug repositioning, along with an extensive example of how researchers can influence therapeutic approaches and further understanding, through either single or multiple disease studies. This paradigm is based on three neurodegenerative diseases with pathophysiological similarities. It is our goal to provide the readers with all the information needed to enrich their research and note expectations along the way.

PMID: 28363518 [PubMed - as supplied by publisher]

Network-based analysis of transcriptional profiles from chemical perturbations experiments.

BMC Bioinformatics. 2017 Mar 23;18(Suppl 5):130

Authors: Mulas F, Li A, Sherr DH, Monti S

Abstract
BACKGROUND: Methods for inference and comparison of biological networks are emerging as powerful tools for the identification of groups of tightly connected genes whose activity may be altered during disease progression or due to chemical perturbations. Connectivity-based comparisons help identify aggregate changes that would be difficult to detect with differential analysis methods comparing individual genes.
METHODS: In this study, we describe a pipeline for network comparison and its application to the analysis of gene expression datasets from chemical perturbation experiments, with the goal of elucidating the modes of actions of the profiled perturbations. We apply our pipeline to the analysis of the DrugMatrix and the TG-GATEs, two of the largest toxicogenomics resources available, containing gene expression measurements for model organisms exposed to hundreds of chemical compounds with varying carcinogenicity and genotoxicity.
RESULTS: Starting from chemical-specific transcriptional networks inferred from these data, we show that the proposed comparative analysis of their associated networks identifies groups of chemicals with similar functions and similar carcinogenicity/genotoxicity profiles. We also show that the in-silico annotation by pathway enrichment analysis of the gene modules with a significant gain or loss of connectivity for specific groups of compounds can reveal molecular pathways significantly associated with the chemical perturbations and their likely modes of action.
CONCLUSIONS: The proposed pipeline for transcriptional network inference and comparison is highly reproducible and allows grouping chemicals with similar functions and carcinogenicity/genotoxicity profiles. In the context of drug discovery or drug repositioning, the methods presented here could help assign new functions to novel or existing drugs, based on the similarity of their associated network with those built for other known compounds. Additionally, the method has broad applicability beyond the uses here described and could be used as an alternative or as a complement to standard approaches of differential gene expression analysis.

PMID: 28361664 [PubMed - in process]

The mortality reducing effect of aspirin in colorectal cancer patients: Interpreting the evidence.

Cancer Treat Rev. 2017 Feb 20;55:120-127

Authors: Frouws MA, van Herk-Sukel MP, Maas HA, Van de Velde CJ, Portielje JE, Liefers GJ, Bastiaannet E

Abstract
In 1971 the first study appeared that suggested a relationship between aspirin and cancer. Currently publications on the subject of aspirin and cancer are numerous, with both a beneficial effect of aspirin on cancer incidence and a beneficial effect on cancer survival. This review focusses on the relation between the use of aspirin and improved survival in colorectal cancer patients. Various study designs have been used, with the main part being observational studies and post hoc meta-analyses of cancer outcomes in cardiovascular prevention trials. The results of these studies are unambiguously pointing towards an effect of aspirin on colorectal cancer survival, and several randomised controlled trials are currently ongoing. Some clinicians feel that the current evidence is conclusive and that the time has come for aspirin to be prescribed as adjuvant therapy. However, until this review, not much attention has been paid to the specific types of bias associated with these studies. One of these biases is confounding by indication, because aspirin is indicated for patients as secondary prevention for cardiovascular disease. This review aims to provide perspective on these biases and provide tools for the interpretation of the current evidence. Albeit promising, the current evidence is not sufficient to already prescribe aspirin as adjuvant therapy for colorectal cancer.

PMID: 28359968 [PubMed - as supplied by publisher]

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

Infect Dis Poverty. 2017 Mar 28;6(1):74

Authors: Bergquist R, Utzinger J, Keiser J

Abstract
The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.

PMID: 28351414 [PubMed - in process]

Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov.

PeerJ. 2017;5:e3154

Authors: Su EW, Sanger TM

Abstract
Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer).

PMID: 28348935 [PubMed - in process]

Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia.

Front Pharmacol. 2017;8:110

Authors: Hamdoun S, Jung P, Efferth T

Abstract
Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 10(5)). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.

PMID: 28344555 [PubMed - in process]

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]