Academic drug discovery: current status and prospects

Everett, Jeremy R.

doi:10.1517/17460441.2015.1059816

Cited by 46 publications

(35 citation statements)

References 49 publications

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“…Efficient drug discovery comprises several systematic steps primarily including in vitro assessment of chemical small compound libraries of bioactive molecules, followed by application of candidate bioactive agents in vertebrate disease modeling organisms and finally clinical application of a promising drug candidate in humans. It is estimated that in this long-lasting and expensive process thousands of bioactive small compounds must be tested to achieve a single therapeutic drug approved for clinical practice [12,13]. Especially, in the early phase, most of the initially tested small compounds drop out due to limited biological impact or severe 'onor off-target' side effects.…”

Section: Aspects and Pitfalls During The Early Phase Of Cardiovasculamentioning

confidence: 99%

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Pott

Rottbauer

Just

2019

Expert Opinion on Drug Discovery

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Introduction: In the last decade, our armamentarium of cardiovascular drug therapy has expanded significantly. Using innovative functional genomics strategies such as genome editing by CRISPR/Cas9 as well as high-throughput assays to identify bioactive small chemical compounds has significantly facilitated elaboration of the underlying pathomechanism in various cardiovascular diseases. However, despite scientific progress approvals for cardiovascular drugs has stagnated significantly compared to other fields of drug discovery and therapy during the past years. Areas covered: In this review, the authors discuss the aspects and pitfalls during the early phase of cardiovascular drug discovery and describe the advantages of zebrafish as an in vivo organism to model human cardiovascular diseases (CVD) as well as an in vivo platform for high-throughput chemical compound screening. They also highlight the emerging, promising techniques of automated read-out systems during high-throughput screening (HTS) for the evaluation of important cardiac functional parameters in zebrafish with the potential to streamline CVD drug discovery. Expert opinion: The successful identification of novel drugs to treat CVD is a major challenge in modern biomedical and clinical research. In this context, the definition of the etiologic fundamentals of human cardiovascular diseases is the prerequisite for an efficient and straightforward drug discovery.

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Section: Aspects and Pitfalls During The Early Phase Of Cardiovasculamentioning

confidence: 99%

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Pott

Rottbauer

Just

2019

Expert Opinion on Drug Discovery

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“…Clearly, it is possible that in natively expressing systems, co‐expressed proteins that are not present in HEK293 cells may alter the pharmacology of a GPCR, as is known for the small group of single transmembrane domain receptor activity modulating proteins (Gingell et al, ; Hay et al, ). However, the structure of ML‐145 contains a central rhodanine fragment, often found in so‐called PAINS (pan‐assay interference compounds) (Everett, ). Thus, it is likely that when used in ex vivo preparations, ML‐145 will have a range of ‘off‐target’ effects that are unappreciated.…”

Section: Gpr35: Ligand Pharmacology and Species Variationmentioning

confidence: 99%

G protein‐coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35

Milligan

2017

British J Pharmacology

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It is widely appreciated that G protein‐coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non‐olfactory G protein‐coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein‐coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein‐coupled receptors in both normal physiology and in the context of disease. ‘Open Innovation’ arrangements, in which pharmaceutical companies and public–private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening ‘hits’ into useful ‘tool’ compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein‐coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein‐coupled receptors, free fatty acid receptor 2 and GPR35.

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“…Given the profound threat these diseases pose, it is fortunate that many academic drug discovery centers, most of them having started within the last decade, actually have a focus on infectious diseases [20–22]. This is perhaps due to the desire to meet unmet medical need, and the need to differentiate the academic efforts from commercial ones and thus not be in direct competition with entities with significantly greater financial resources.…”

Section: Aimmentioning

confidence: 99%

Consortia’s Critical Role in Developing Medical Countermeasures for re-emerging Viral Infections: A Usa Perspective

et al. 2016

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Viral infections, such as Ebola, severe acute respiratory syndrome/Middle East respiratory syndrome and West Nile virus have emerged as a serious health threat with no effective therapies. These infections have little commercial potential and are not a high priority for the pharmaceutical industry. However, the academic community has been active in this area for many years. The challenge is how to take this academic virology knowledge into a drug discovery and development domain. One approach is the use of consortia and public–private partnerships – this article highlights ongoing efforts in the USA. Public funds, such as those from government sources, can support research efforts that do not to appear to have commercial value. The key to success is finding a way to combine the different cultural and operational values and reward systems into a productive collaboration to identify new antivirals.

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Academic drug discovery: current status and prospects

Cited by 46 publications

References 49 publications

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Streamlining drug discovery assays for cardiovascular disease using zebrafish

G protein‐coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35

Consortia’s Critical Role in Developing Medical Countermeasures for re-emerging Viral Infections: A Usa Perspective

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