Finding Relevant Hits to Progress Drug Discovery Programs

Drug discovery success starts with an active hit compound. Implementing a good hit identification approach like high-throughput screening at the beginning of a project can help companies advance their programs without unexpected costs and delays.

The hit finding process – identifying a compound that acts on a biological target – is perhaps the single most crucial step in drug discovery, and often fails to get the attention it deserves. Regardless of whether the goal is to find small or large molecule drug candidates, medicinal chemists and protein engineers need to start with active compounds to improve and optimize into leads worthy of further development.

The many approaches to hit identification

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Kevin Nash, Group Leader in Biology Assay Development High-Throughput Screening, Charles River Laboratories

Various approaches can be used alone or in combination to find hits and confirm the activity of compounds of interest. Each comes with its own benefits.

“High-throughput screening of diverse compound libraries can accelerate the discovery process,” said Kevin Nash, Group Leader in Biology Assay Development High-Throughput Screening at Charles River Laboratories. “You can screen a large number of compounds in a relatively short time, and this increases your chance of finding the hit material that has your biological activity of interest.”

The use of cell-based assays that look for a desired phenotypic change, such as altered gene expression or cell viability, is another approach that can help identify compounds that are active against unknown disease targets.

Screening a focused compound library directed against specific target classes or a fragment-based approach can identify compounds that are active against or bind to the target of interest. A computational approach can focus the screening efforts on specific chemical scaffolds and prioritize compounds for further experimental investigation. 

Developing the right assay for high-throughput screening is key

Regardless of the approach, it is essential to consider what will happen after the screening campaign and to start with a relevant assay, which will actually identify the desired hits. It is critical to fully understand each assay’s capabilities and limitations because the chosen screening assay becomes the cornerstone for the entire drug discovery cascade. 

“One of the biggest challenges in hit finding is making sure you develop the right assay for your high-throughput screen,” explained Nash. “You need to have an idea of what kind of compounds you want to identify in the screen and then configure the assay so that it leads you in the right direction.”

Starting a high-throughput screening campaign with the wrong assay can lead the discovery effort down an expensive and time-consuming path. And in the end, the hits identified through the screen may not even reflect the biological effect of interest. 

“It’s important to implement orthogonal assays after the initial screen that can distinguish potential false-positives that might interfere with your setup,” said Nash. “When you do this, you can be quite certain at the end of the campaign that your hits are genuinely acting on your target.”

Increasing success through a strategic partnership

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Ian Waddell, Chief Scientific Officer, Charles River Laboratories

Collaborating with a knowledgeable partner like Charles River Laboratories can help companies develop a good hit-finding approach, avoid pitfalls, and ensure that the hits they identify are of high quality. Charles River’s drug discovery experts support the hit identification process and the subsequent steps in the drug discovery workflow. 

When it comes to high-throughput screening, Charles River executes traditional, predesigned assays and also develops and implements fully customized assays against challenging targets. For example, finding hits against DNA or RNA biomarkers requires a deep understanding of the target biology, so scientists can make informed decisions regarding the best assay type and the most relevant compound libraries to screen.

“Our scientists are highly experienced in working with diverse targets and assay formats,” said Ian Waddell, Chief Scientific Officer at Charles River. “They understand the potential liabilities and challenges and can recommend a successful course of action.”

This experience includes the development of cell-based assays for phenotypic screening, a strategy that enables the identification of hits against unknown targets. 

Phenotypic screening may range from simple cell proliferation or viability assays to more complex, multicellular assays involving high-content imaging. This screening approach can be useful in a range of therapeutic areas, including oncology, diabetes, and neurodegeneration.

In vitro assays that mimic the complexity of a biological environment are more predictive of how a compound will respond in vivo,” explained Waddell. “These assays can accelerate drug discovery by delivering the right candidate with the most relevant biological effect.”

Deciding which compounds to screen with the assay is also important. Charles River offers screening of a diverse collection of compound libraries, including its own or those of its partners. The computer-aided drug design team can narrow-down the selection of compounds to screen based on parameters important to the project.

Charles River’s drug discovery expertise extends beyond the initial screening phase. Its scientists also offer hit expansion, hit-to-lead, and medicinal chemistry support to help its partners meet tight timelines and make the most of their budget.

“In hit finding, what’s important is the quality of the hit, not the quantity,” said Waddell. “The entities must be relevant to the biological question, and they must be able to progress through the drug development process, to IND, and eventually on to patients.”

Visit Charles River Laboratories to find out more about its high-throughput screening and phenotypic screening services.


Header image via Shutterstock.com and all other images via Charles River Laboratories.

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