Novel insight into drug repositioning: Methylthiouracil as a case in point

Baek, Moon‐Chang; Jung, Byeongjin; Kang, Hyejin; Lee, Hyun‐Shik; Bae, Jong‐Sup

doi:10.1016/j.phrs.2015.06.008

Cited by 17 publications

(9 citation statements)

References 90 publications

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“…Repurposing can be distinguished from repositioning in which a non-approved agent in a sponsor’s development program changes from one indication to another because disease-related, compound-related, or commercial circumstances suggest that success in further development may be more likely in one condition than another [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposed agents in the Alzheimer’s disease drug development pipeline

2020

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Background Treatments are needed to address the growing prevalence of Alzheimer’s disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes. Methods We assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020. Results We identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov. Conclusions Drug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

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Section: Discussionmentioning

confidence: 99%

Repurposed agents in the Alzheimer’s disease drug development pipeline

2020

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“…Compared with the development of new drugs, novel applications of established drugs could reduce risks and have obvious advantages for the treatment of refractory diseases (Baek et al, 2015). For example, based on protein interactions, several clinical drugs have been evaluated for the treatment of COVID-19, avoiding time-consuming and expensive drug development (Gordon et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Repurposing of Pirfenidone (Anti-Pulmonary Fibrosis Drug) for Treatment of Rheumatoid Arthritis

Gan

Cheng

et al. 2021

Front. Pharmacol.

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Clinical studies have shown that pirfenidone (PFD) effectively relieves joint pain in rheumatoid arthritis (RA) patients. However, the detailed mechanisms underlying the anti-RA effects of PFD have not been investigated. This study was undertaken to investigate the repurposing of PFD for the treatment of RA, and explore its anti-rheumatic mechanisms. A collagen-induced arthritis (CIA) rat model was used to observe joint pathological changes following PFD treatment. Based on bioinformatics to predict the mechanism of PFD anti-RA, using EA. hy926 and TNF-α-induced MH7A cells to establish in vitro model to explore its biological mechanism from the perspectives of synovial inflammation and angiogenesis. PFD significantly relieved pathological changes, including joint swelling, synovial hyperplasia, inflammatory cell infiltration and joint destruction. PFD was also associated with reduced expression of MMP-3 and VEGF in articular chondrocytes and synovial cells of CIA rats (p < 0.05). Using bioinformatic methods, we predicted that PFD inhibits cell inflammation and migration by interfering with the JAK2/STAT3 and Akt pathways. These results were verified using in vitro models. In particular, PFD effectively reduced the expression of pro-inflammatory, chondrogenic, and angiogenic cytokines, such as IL-1β, IL-6, IL-8, MMP-1/3/2/9 and VEGF (p < 0.05), in TNF-α-induced MH7A cells. In addition, PFD significantly reduced the production of MMP-2/9 and VEGF in EA. hy926 cells, thereby weakening migration and inhibiting angiogenesis (p < 0.05). These findings suggest that PFD may alleviate the pathological process in CIA rats, by inhibiting inflammation and angiogenesis through multiple pathways, and serve as a potential therapeutic drug for RA.

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Section: Introductionmentioning

confidence: 99%

“…The traditional drug discovery process, with the design and validation of new chemicals, is a time-consuming and expensive process [1][2][3]. Despite the investment in drug discovery, the number of new drugs identified by this classic approach has not increased significantly in the past [1]. Another approach is drug repositioning, which involves identifying new chemicals from old drugs and applying the newly identified drugs to the treatment of a disease other than the drug's intended disease [4].…”

Section: Introductionmentioning

confidence: 99%

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury

Lee

Baek

Kim

et al. 2020

IJMS

Self Cite

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The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.

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Novel insight into drug repositioning: Methylthiouracil as a case in point

Cited by 17 publications

References 90 publications

Repurposed agents in the Alzheimer’s disease drug development pipeline

Repurposed agents in the Alzheimer’s disease drug development pipeline

Repurposing of Pirfenidone (Anti-Pulmonary Fibrosis Drug) for Treatment of Rheumatoid Arthritis

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury

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