Strategy Of Drug Repurposing Research Articles

Repurposed drug candidates for antituberculosis therapy

Antibiotics have been a key part of clinical treatments for more than 70 years. Long-term use of antimicrobial treatments has led to the development of severe bacterial resistance, which has become increasingly serious due to antibiotic abuse, resulting in the treatment of bacterial infections becoming challenging. The repurposing of approved drugs presents a promising strategy to address current bottlenecks in the development of novel antibacterial agents. Drug repurposing is a cost-effective emerging strategy, which aims to treat resistant infectious diseases by identifying known drugs with predicted efficacy for diseases other than the target disease. This strategy has potential in the treatment of tuberculosis (TB), particularly drug-resistant TB. In recent years, a panel of drugs approved for clinical use or clinical trials, such as linezolid, vancomycin and celecoxib, have been found to have anti-TB activities. However, the utility of drug repurposing is limited by the number of candidate compounds and their low activities. The low activities of repurposed drugs have slowed the development of a drug-repurposing strategy for anti-TB drugs. The present review discusses progress in the discovery of new anti-TB agents through drug repurposing since 2014. We also discuss the challenges faced and analyze the innovative ways that are being used to overcome these difficulties. This review may provide a useful guide for researchers in the field of drug repurposing.

Multifunctional compounds lithium chloride and methylene Blue attenuate the negative effects of diisopropylfluorophosphate on axonal transport in rat cortical neurons

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).

The Thiol-polyamine Metabolism of Trypanosoma cruzi: Molecular Targets and Drug Repurposing Strategies.

Chagas´ disease continues to be a challenging and neglected public health problem in many American countries. The etiologic agent, Trypanosoma cruzi, develops intracellularly in the mammalian host, which hinders treatment efficacy. Progress in the knowledge of parasite biology and host-pathogen interaction has not been paralleled by the development of novel, safe and effective therapeutic options. It is then urgent to seek for novel therapeutic candidates and to implement drug discovery strategies that may accelerate the discovery process. The most appealing targets for pharmacological intervention are those essential for the pathogen and, whenever possible, absent or significantly different from the host homolog. The thiol-polyamine metabolism of T. cruzi offers interesting candidates for a rational design of selective drugs. In this respect, here we critically review the state of the art of the thiolpolyamine metabolism of T. cruzi and the pharmacological potential of its components. On the other hand, drug repurposing emerged as a valid strategy to identify new biological activities for drugs in clinical use, while significantly shortening the long time and high cost associated with de novo drug discovery approaches. Thus, we also discuss the different drug repurposing strategies available with a special emphasis in their applications to the identification of drug candidates targeting essential components of the thiol-polyamine metabolism of T. cruzi.

Computational Drug Repurposing: Current Trends.

Biomedical discovery has been reshaped upon the exploding digitization of data which can be retrieved from a number of sources, ranging from clinical pharmacology to cheminformatics-driven databases. Now, supercomputing platforms and publicly available resources such as biological, physicochemical, and clinical data, can all be integrated to construct a detailed map of signaling pathways and drug mechanisms of action in relation to drug candidates. Recent advancements in computer-aided data mining have facilitated analyses of 'big data' approaches and the discovery of new indications for pre-existing drugs has been accelerated. Linking gene-phenotype associations to predict novel drug-disease signatures or incorporating molecular structure information of drugs and protein targets with other kinds of data derived from systems biology provide great potential to accelerate drug discovery and improve the success of drug repurposing attempts. In this review, we highlight commonly used computational drug repurposing strategies, including bioinformatics and cheminformatics tools, to integrate large-scale data emerging from the systems biology, and consider both the challenges and opportunities of using this approach. Moreover, we provide successful examples and case studies that combined various in silico drug-repurposing strategies to predict potential novel uses for known therapeutics.

Discovery of Candesartan Cilexetic as a Novel Neddylation Inhibitor for Suppressing Tumor Growth

Background: Protein neddylation is a posttranslational modification of conjugating the neuronal precursor cell-expressed developmentally down-regulated protein 8 (Nedd8) to substrates. The best characterized substrates of neddylation are cullin family members, the essential components of cullin-RING E3 ubiquitin ligases (CRLs). Previous studies have shown that the neddylation pathway is overactivated in various types of human cancers and correlates with the disease progression, whereas pharmacologically targeting this pathway has emerged as an attractive therapeutic strategy. Methods: To screen the potential neddylation inhibitors for anticancer therapy, the inhibitory effects on neddylation modification of 1331 approved drugs were investigated by an improved enzyme-based assay. Neddylation inhibiting mechanism of hit compound was illuminated by exploring the levels of Nedd8 modification on cullins and the subsequent changes of CRLs substrates in enzyme- and cellular-based assays, along with the molecular docking of hit compound with the target neddylation enzyme. A series of phenotypic experiments, including assays on in vitro cell proliferation, cell cycle arrest and in vivo tumor growth, were applied to investigate the anticancer activities and mechanisms of hit compound. Findings: An antihypertensive agent candesartan cilexetic (CDC) was identified as a new neddylation inhibitor from 1331 approved drugs based on the strategy of drug repurposing. CDC inhibited neddylation pathway by ATP-competitively suppressing Nedd8-activating enzyme (NAE, E1), which was superior to two representative non-covalent NAE inhibitors, M22 and mitoxantrone. Following with the findings such as apoptotic induction and tumor growth suppression, CDC represents a potential antitumor lead compound with promising neddylation inhibitory activity. Interpretation: In this study, we identified CDC as a hit compound that blocks the neddylation modification of cullins. Our findings highlighted the potential of developing CDC as a novel neddylation inhibitor. Funding Statement: This work was supported by the Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81625018, 81820108022), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All experimental protocols were approved by the Animal Experimental Ethics Committee of Longhua Hospital of Shanghai University of Traditional Chinese Medicine.

Impact of levamisole in co-administration with benznidazole on experimental Chagas disease.

Levamisole (Lms) is an anthelminthic drug with immunomodulatory activity. Chagas disease (CD) is caused by Trypanosoma cruzi and there is very low access to the drugs available, benznidazole (Bz) and nifurtimox, both far from ideal. In a drug-repurposing strategy to test potential activity as antiparasitic and immunomodulatory agent for CD, Lms was assayed on acute T. cruzi murine infection, alone and in co-administration with Bz. During protocol standardization, 100 and 10 mpk of Bz given for five consecutive days resulted in parasitaemia suppression and 100% animal survival only with the highest dose. Flow cytometry showed that both optimal (100 mpk) and suboptimal (10 mpk) doses of Bz equally decreased the plasma levels of cytokines commonly elevated in this acute infection model. Lms alone (10-0.5 mpk) did not decrease parasitaemia nor mortality rates. Co-administration was investigated using the suboptimal dose of Bz and different doses of Lms. While Bz 10 mpk did not alter parasitaemia, the combo partially reduced it but only slightly promoted animal survival. This effect could be related to Th1-response modulation since interleukin-6 and interferon-γ were higher after treatment with the combo.

Toward a Reasoned Classification of Diseases Using Physico-Chemical Based Phenotypes.

Background: Diseases and health conditions have been classified according to anatomical site, etiological, and clinical criteria. Physico-chemical mechanisms underlying the biology of diseases, such as the flow of energy through cells and tissues, have been often overlooked in classification systems.Objective: We propose a conceptual framework toward the development of an energy-oriented classification of diseases, based on the principles of physical chemistry.Methods: A review of literature on the physical chemistry of biological interactions in a number of diseases is traced from the point of view of the fluid and solid mechanics, electricity, and chemistry.Results: We found consistent evidence in literature of decreased and/or increased physical and chemical forces intertwined with biological processes of numerous diseases, which allowed the identification of mechanical, electric and chemical phenotypes of diseases.Discussion: Biological mechanisms of diseases need to be evaluated and integrated into more comprehensive theories that should account with principles of physics and chemistry. A hypothetical model is proposed relating the natural history of diseases to mechanical stress, electric field, and chemical equilibria (ATP) changes. The present perspective toward an innovative disease classification may improve drug-repurposing strategies in the future.

Repositioning of drugs using open-access data portal DTome: A test case with probenecid (Review).

The one gene-one enzyme hypothesis, first introduced by Beadle and Tatum in the 1940s and based on their genetic analysis and observation of phenotype changes in Neurospora crassa challenged by various experimental conditions, has witnessed significant advances in recent decades. Much of our understanding of the association between genes and their phenotype expression has benefited from the completion of the human genome project, and has shown continual transformation guided by the effort directed at the annotation and characterization of human genes. Similarly, the idea of one drug‑one primary disease indication that traditionally has been the benchmark for the labeling and usage of drugs has also undergone evident progressive refinements; in recent years the science and practice of pharmaceutical development has notable success in the strategy of drug repurposing. Drug repurposing is an innovative approach where, instead of denovo synthesis and discovery of new drugs with novel indications, drug candidates with the desired usage are identified by a process of re‑profiling using an open‑source database or knowledge of known or failed drugs already in existence. In the present study, the repurposing drug strategy employing open‑access data portal drug‑target interactome (DTome) is applied to the uncovering of new clinical usage for probenecid.

Biomarker-Guided Repurposing of Chemotherapeutic Drugs for Cancer Therapy: A Novel Strategy in Drug Development

Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point.

Rational Design of a Therapeutic Program for Multiple Myeloma Using a Strategy of Drug Repurposing and Combination Therapy

AbstractAbstract 5022 Background:The extremely long development time and low success rate for new drug development programs has translated into limited clinical options in the treatment of cancer. The challenge is further compounded by drug resistance seen in clinical settings for approved standard of care therapeutic options like chemotherapy and targeted drugs like Bortezomib in Multiple Myeloma (MM). This has accelerated the need for initiatives and strategies which promote innovation but drastically reduce drug development failures through prediction of clinical outcomes. We present here a methodology and rationally designed therapeutic program for MM. This program has novel first-in-class mechanism of action and has been developed using a strategy of re-purposing and combinations based on National Center for Advanced Translational Sciences (NCATS) library of industry-provided drugs. Methods:The therapy design and development was completed using validated proprietary technology from Cellworks which enables simulation of cancer disease physiology computationally for predicting clinical outcomes. The comprehensive integrated representation of signaling and metabolic networks across all disease phenotypes and functional proteomics abstraction facilitated a large number of predictive studies in weeks with quantitative transparency into the network. The predictive cancer technology was customized to four MM profiles: OPM2, RPM1, SKMM2 and U266. Ten of the molecularly targeted drugs from the NCATS library were digitally screened alone and in combinations of two across the four MM profiles at four concentrations (C, C/2, C/4, and C/8). Based on screening of over six thousand predictive studies, three designed therapeutics hits were intelligently shortlisted based on synergistic impact on viability and proliferation. Results:The focused therapeutic candidate hit was selected based on synergy using viability endpoints and apoptosis markers such as caspase 3, PARP1 at sub-therapeutic doses. The proposed therapeutic regimen is a sub-therapeutic combination of AT101 and AVE0847. AT101 is a BCL2 inhibitor and AVE0847 is a PPAR alpha and gamma agonist agent. The concentration of each drug used in the designed therapy was close to IC30. The predictive results showed a synergistic increase in apoptotic markers caspase 3 and PARP1 cleaved form. This hit candidate is being pre-clinically validated experimentally across four MM profiles and results will be presented.Table 1:Showing the impact on viability phenotype and apoptotic biomarker caspase 3 with the IC30 combination of the two drugs.PhenotypesU266OPM2SKMMRPMIViability−58.96−62.71−55.39−69.64Caspase 3+90.26+132.67+69.31+202.91 Conclusion:The design of first in class mechanism of action based therapeutic strategies of drug rescue/repurposing has been used to identify AT101 and AVE0847 as a promising drug combination for use in MM which predicatively results in a synergistic increase in apoptosis. These results are currently being validated in vitro. The inherent multi target mechanism of action predicted by this combination could potentially eliminate the drug resistance challenges of single target therapeutics. Disclosures:No relevant conflicts of interest to declare.

Is repositioning of drugs a viable alternative in the treatment of tuberculosis?

Antimicrobial resistance is a serious problem because of the scarcity of new antibiotics effective against pathogens such as methicillin-resistant Staphylococcus aureus, β-lactamase-producing Gram-negative bacteria and multidrug-resistant Mycobacterium tuberculosis. Extensively drug resistance is particularly worrying in tuberculosis (TB), since the causative bacteria have become resistant to almost all available first- and second-line drugs and resistance is a threat to achieving control of the disease. Development of new drugs is a lengthy and costly endeavour. This is a particular problem for antibiotics, usage of which is likely to be of limited duration, and is even more true of antibiotics whose use is restricted to the treatment of a disease, such as TB, that is considered to be 'poverty related', and for which the return on the investment is seen as non-attractive. In spite of this, there is an emerging pipeline of new drugs under development that hopefully will bring new anti-TB drugs to the market in the near future. The strategy of drug repurposing, finding new uses for existing approved medicines, has seen unexpected success in other medical areas. More than one blockbuster drug has originated from this strategy. And in the field of TB, there have been several examples in recent years of this approach leading to the use of drugs for which there is undeniable evidence of efficacy in the treatment of the disease, the best example being the fluoroquinolones, which were not developed originally to treat TB. This article reviews some examples of repurposing of drugs in the treatment of TB, newer candidates for repurposing for which there is already preliminary evidence of activity and possible new options that merit further investigation.

Abstract B47: Pleiotropic effects of simvastatin on prostate tumor growth and metastasis

Abstract Background: Statins are a class of drugs that inhibits HMG-CoA reductase, a rate liming enzyme in cholesterol synthesis. Simvastatin, a widely used generic drug for preventing cardiovascular events inhibit inflammation and stabilize atherosclerotic plaques. Growing body of evidences suggest that statins have the potential to reduce the risk of many cancer types. Objectives and Hypothesis: Our long-term goal is to enable the development of new and innovative therapeutics for prostate cancer through better understanding of the molecular mechanisms regulating prostate cancer growth and bone metastasis. In prostate cancer cells, simvastatin is known to induce apoptosis. Akt, a multitask signaling molecule, is the major survival kinase activated in cancer cells. Our central hypothesis is that treatment with simvastatin will inhibit Akt affecting prostate cancer cell function, tumor growth and metastasis. The rationale for the proposed research is that, once it is known mechanistically how simvastatin regulates prostate cancer cell function, it is likely that prostate tumor growth and metastasis can be downregulated therapeutically utilizing simvastatin using a novel drug-repurposing strategy. This would be of singular importance in the management of this disease. Experimental Design and Results: In the current study, we sought to investigate the pleiotropic effects of simvastatin on major signaling pathways in prostate cancer cells with respect to the regulation of cellular functions such as migration, proliferation, colony/foci formation and invasion, along with its already known effects on apoptosis. Time- and dose-effects of simvastatin on LNCaP (androgen-dependent) and PC-3 (androgen-independent) cells indicated that treatment with as low as 25µM simvastatin was sufficient to inhibit serum-stimulated activation of Akt-mTOR and cRaf-ERK pathways. Akin to this, treatment with 25µM simvastatin significantly inhibited serum- and EGF-induced cell migration, invasion, colony formation and proliferation. Simvastatin-mediated effects on cell migration and colony formation was rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in androgen-independent prostate cancer cells lines such as PC3 and LnCAP C4-2. A xenograft model performed in nude mice exhibited reduced PC3 prostate tumor growth with simvastatin treatment (2mg/kg body weight/day for 2 weeks) demonstrating the therapeutic potential of simvastatin for prostate cancer therapy. Conclusions and Future Directions: Our findings suggest a link between simvastatin and Akt/ERK signaling in the regulation of prostate cancer growth and metastasis. Further investigation is currently underway in our laboratory to unravel the molecular mechanisms on simvastatin-mediated effects on prostate cancer leading to tumor growth and bone metastasis in vivo using transgenic mouse models such as AKt+ and TRAMP+ mice. We also plan to undertake a clinical study on patients with prostate cancer who were on statin treatment prior to and after diagnosis and analyze biopsy specimen from these patients. A prospective study will look at the role statins in prostate cancer prevention and/or on management. Our ultimate aim is to investigate if statins can be used as an adjuvant drug in the treatment of patients already diagnosed with prostate cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B47.