Repurposing Strategies for Therapeutics

Sleigh, Sara; Barton, Cheryl L.

doi:10.1007/bf03256811

Cited by 130 publications

(96 citation statements)

References 5 publications

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“…Thus, several types of repurposing models emerge: large pharmaceutical houses, major clinical enterprises, governmental facilities, and consortia involving (mostly) academic groups in partnership with industry interested in niche therapeutic areas. Recent strategic approaches and individual companies that currently engage in drug repurposing as their primary business platform have been reviewed elsewhere [37].…”

Section: Who's Who In Drug Repurposingmentioning

confidence: 99%

Drug Repurposing: Far Beyond New Targets for Old Drugs

Oprea

Mestres

2012

AAPS J

232

138

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Abstract. Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug-target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.KEY WORDS: drug repurposing; drug-target interactions; intellectual property; side effect tolerance; target identification.There are two major "unknown unknown" categories in drug discovery [1] that can be linked to the main reasons for failure in drug approval, namely safety and efficacy [2]. The first category is related to the toxicological and pharmacokinetic profiles of the new molecular entity (NME), and it is mainly addressed in phases I and IIa clinical trials, following multiple preclinical evaluations: these evaluate the therapeutic regimen (i.e., dose and frequency) and safety aspects concerned to the NME. The second category relates to the protein target and biological pathway that are subject to therapeutic interference, and it is indirectly linked to the clinical efficacy of the NME under investigation: in this case, the question being addressed is whether the NME-induced perturbation of the chosen (hypothesized) target or pathway leads to the desired clinical effect [3]. The uncertainty related to the unknown unknown aspect of discovery is often mitigated by eliminating some of the "unknown" elements: either the NME is well understood, i.e., an approved drug [4], or the target/pathway is well described, i.e., already successfully manipulated therapeutically [5]. Preferably, both "unknowns" have been addressed previously, with the expectation that derisking the discovery aspect may lead to a higher success rate.The unknown unknown strategy has been rewarding, as many blockbuster franchises have emerged following this recipe, e.g., histamine H2 antagonists, proton pump inhibitors, anticoagulant/antithrombotic therapy, or drugs to reduce hypercholesterolemia [6]. However, such drugs are the result of a long, high-cost, and high-risk optimization process, often subject to "fast followers," where first-in-class does not equate with the most financially rewarding NME [7]. In order to reduce time-to-market, as well as associated costs and risks, alternat...

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Section: Who's Who In Drug Repurposingmentioning

confidence: 99%

Drug Repurposing: Far Beyond New Targets for Old Drugs

Oprea

Mestres

2012

AAPS J

232

138

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“…33 Recently, it has been shown that the rate of production of novel drugs has changed little since the 1950s, 28 yet the cost of developing those drugs has soared. As a result, pharmacological research increasingly focuses on repurposing or repositioning existing drugs for new indications.…”

Section: Drug Discovery and Drug Repurposingmentioning

confidence: 99%

“…33 Approaches to drugrepurposing include database-driven bioinformatics approaches, in vivo and ex vivo studies as well as high-throughput screening methods. 33 Finding new targets for existing drugs depends on our fundamental understanding of the physiology and pathobiology that underlies diseases, their phenotypic manifestations and the molecular sites of action of small-molecule therapeutics. The manifest modularity of disease phenotypes reflects the existence of underlying physiological pathways, and a lesion in any of the components of the same pathway can produce closely overlapping disease phenotypes.…”

Section: Drug Discovery and Drug Repurposingmentioning

confidence: 99%

Linking Pharmgkb to Phenotype Studies and Animal Models of Disease for Drug Repurposing

et al. 2011

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The investigation of phenotypes in model organisms has the potential to reveal the molecular mechanisms underlying disease. The large-scale comparative analysis of phenotypes across species can reveal novel associations between genotypes and diseases. We use the PhenomeNET network of phenotypic similarity to suggest genotype-disease association, combine them with drug-gene associations available from the PharmGKB database, and infer novel associations between drugs and diseases. We evaluate and quantify our results based on our method's capability to reproduce known drug-disease associations. We find and discuss evidence that levonorgestrel, tretinoin and estradiol are associated with cystic fibrosis (p < 2.65 · 10 −6 , p < 0.002 and p < 0.031, Wilcoxon signedrank test, Bonferroni correction) and that ibuprofen may be active in chronic lymphocytic leukemia (p < 2.63 · 10 −23 , Wilcoxon signed-rank test, Bonferroni correction). To enable access to our results, we implement a web server and make our raw data freely available. Our results are the first steps in implementing an integrated system for the analysis and prediction of drug-disease associations for rare and orphan diseases for which the molecular basis is not known.

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Altering the core skeleton and substituents on free alcohol of aspergillides resulted in improved biological activity [1][2][3][4][5][6][7][8] .Based on the biological evaluation results and as part of our ongoing projects in this area we became interested to design and synthesize some analogues by altering the core skeleton and the substituents on pyran ring alcohol which are expected to be more potent than the parent aspergillide. Objective of the current work is to prepare novel13 membered aspergillide analogues.

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mentioning

confidence: 99%

“…Altering the core skeleton and substituents on free alcohol of aspergillides resulted in improved biological activity [1][2][3][4][5][6][7][8] .…”

mentioning

confidence: 99%