Webinar highlights: Recent advances in diagnostics and treatments – from small molecules to cellular therapies

A project that progressed from Target Identification through to Drug Approval was illustrated by PCSK9, a novel cardiovascular disease target. Finally, examples of experimental techniques to accelerate, de-risk and identify off-target effects at an early stage in drug discovery were discussed.

During the webinar held on 16 October, Sheraz Gul, Head of Drug Discovery at the Fraunhofer Institute for Molecular Biology and Applied Ecology presented pre-clinical milestones and a novel CVD target.

Pan-assay interference compounds (or PAINs) are an important consideration for in vitro HTS assays because they can lead to false positives. Is this a similar problem for cell-based assays and what can we do to prevent false positives?

A typical screening campaign that makes use of cell-based assays generally delivers weakly active hits with IC50 in the low micromolar range. A major issue with this is the associated compound mediated cytotoxicity, which might correlate with PAINS. As a consequence, it is necessary to determine to what extent any observation is related to the desired drug target and the undesired off-target effects that could underlie the observation. The experimental work required at this stage to identify the most promising compounds to progress is time consuming. As a minimum, a robust cellular toxicity assay should be used post screening to triage hits. It is noteworthy that many known drugs exhibit cellular toxicity, therefore this type of assay should be used to flag compounds rather than discard them wholesale.

For a new lab getting into the area of cell-based, phenotypic screening, what are the major bottlenecks with setting up the assays and what is the best way to overcome them?

The time taken to develop screening compatible assays and running screening campaigns has reduced considerably. This is due in part to the commercial availability of many fit-for-purpose screening compatible assays for the major drug target classes. For example, more than 20 different such kinase assays are available in the marketplace. Many methods are available to screen assays eg, collaborative or fee-for-service basis. Developing an assay in-house requires suitable hardware and trained scientists who are able to trouble-shoot technical issues that arise during the experimental work.

To what extent do you think ‘open’ drug discovery, and particularly, not patenting early tool compounds, aids the tractability assessment of new drug targets?

The term “open drug discovery” was coined some time ago and many such initiatives have been created to enable collaboration and accelerate drug discovery. One of the largest such projects is the Innovative Medicines Initiative (IMI), which is a partnership between the European Union and the European pharmaceutical industry. It facilitates open collaboration to advance healthcare needs including drug discovery and accelerating patient access to personalised medicines. The IMI projects involve key players of healthcare research such as universities, research centres, the pharmaceutical and other industries, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. It is clear from the scale of the IMI and its achievements, “open drug discovery” will continue and adapt.

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