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Rational Screen Design: A Long-Lived Topic

“Could I have found this compound faster, cheaper or easier by an alternative strategy?” This is a question anyone involved in running a screening campaign should ask themselves, says Ed Ainscow, head of discovery at Carrick Therapeutics and chair of the SLAS2017 Rational Screen Design Session in the Assay Development and Screening Track

This question has been posed since drug discovery began, and the advent of high-throughput screening made it a more pressing question.

By The Lab Man

(AKA SLAS Director of Education Steve Hamilton, Ph.D.)

“Fundamentally there is always a challenge in any screen to make sure you are finding the best lead candidates from a wide range of potential chemical space – and to do that in a speedy and cost efficient manner,” Ainscow feels. “Rational or intelligent screen design is an approach that uses one or more known attributes of either the screening system or the compound library to offer an alternative to the brute force approach of screening vast libraries of compounds.

“Rational design is becoming more relevant in today’s screening environment because of the types of assays that we are now running,” Ainscow continues. “For example, at SLAS2017, participants will hear about a number of screens that utilize iPSCs (induced pluripotent stem cells) differentiated into a variety of cell types such as cardiomyocytes or hepatocytes. Often the complexity in growing and culturing these cells to their differentiated state means that a screen of a few 10s of plates is all that can be achieved. Researchers need to make sure they are maximizing the use of these cells to provide useful leads and that is where rational screen design can help.”

High-throughput screening for drug discovery has been in use for 20+ years and many different approaches have been tried. “Traditionally, there has been a mentality that bigger is better regarding screening and that golden nugget of a hit may come from anywhere in your library,” says Ainscow. “I personally know of cases where a singleton hit has led to a successful candidate drug selection, but those cases tend to be the exception rather than the rule.“ Ainscow’s screening experience at The Genomics Institute of the Novartis Research Foundation (GNF) and at AstraZeneca has led him to feel, “In contrast, screening more, faster and cheaper is really only an option for a subset of target-based assays and what we have learned over the years is that this is not always the best strategy to find drugs – particularly those that act through a novel mechanism of action. Similarly, the best hits from screens, those that get chemists excited, tend to come from classes of similar molecules with a range of activity that show a structure activity relationship.”

Supporting Technologies

Related technologies, such as informatics – particularly cheminformatics – play important roles in rational screening. Scientists must look at compound structure-activity relationships together with retrospective analyses of screening databases to propose which part of chemical space is most likely to generate leads. Combination screening presents a related but different challenge. Here the advent of automation technologies such as acoustic dispensing and cellular profiling platforms have been critical in enabling screen designs that can sparsely sample compound space at varying concentrations across many cellular models which is critical in identifying robust synergistic interactions.

Ainscow notes that designs will vary for various types of screening. “For many biochemical approaches, the standard approaches of miniaturization and automation mean that, in most cases, you can screen any size of library in a cost efficient and timely manner. Even libraries of several millions of compounds can be screened in a few weeks, and for less than a penny a well. However other screening formats can run into limitations with large libraries. These can come in the shape of cost, such as in expensive plates for biophysical readouts, the complexity of providing cellular models for iPSC or 3D organotypic models, restrictions in the throughput of assay readout, for example in flow cytometry or gene expression assays, or just in the sheer size of chemical space that could be tested as in combinatorial screening.” 

Rational Screen Design at SLAS2017, Feb. 4-8, Washington, DC                 

The Rational Screen Design Session at SLAS2017 consists of four highly respected speakers. Ainscow offers insight into these upcoming presentations:

Patrycja Nowak-Sliwinska
University of Geneva, Switzerland and JALA Editorial Board Member
Phenotypic Personalized Medicine as a Powerful Discovery Platform for the Optimization of Multidrug Treatments for Cancer

Selecting the right compound and combinations for the right patient is the central tenant of personalized healthcare. It promises to deliver the appropriate targeted therapy to those who will benefit most. The first wave of personalized healthcare has been driven by matching genetic mutations in cancers to selective therapeutics. However, even in a well studied field such as lung cancer, only about half of cancers are caused by known driver mutations.

An alternative method is to use the phenotypic response of patient derived cells to a range of targeted agents to inform which therapies are going to the most efficacious. Nowak-Sliwinska has taken such an approach and combined it with iterative analysis based on design of experiments to identify optimized drug combinations and doses that show a synergistic response. This could potentially be used to rapidly profile combinations as a precision tool against cancer.

Fred King
The Genomics Institute of the Novartis Research Foundation (GNF), La Jolla, CA
Rational Design in Combination Screening

The numbers involved in combinatorial screening can be a headache even when the focus is on pairs of compounds. When scientists start going into higher orders of compounds such as three, four or five compounds, the numbers really become scary. Yet standard combination therapies in oncology and other settings routinely have multiple components (e.g., the standard of care for non-Hodgkin lymphoma is a cocktail of four molecules).

King describes an approach to surveying higher order combination space and how this has been applied to screen for synergy in killing cancer cell lines. It is an interesting experiment in how a tiered screening approach can be used to find the most active compound combinations. Of course, such screens are only as good as the starting material; in this case the set of bioactive compounds used in the synergy search. King also talks about his approach for characterizing and selecting compounds of diverse bioactivity.

Louis Scampavia
The Scripps Research Institute, Florida Campus
Fragment-Based Assisted HTS: A Novel Approach to Traditional Drug Discovery

Fragment-based drug discovery has been around for some time, but has been for the most part a sideline activity for most HTS groups due to long development times of compounds and relatively poor efficacy of the hits compared to larger molecules found in most compound libraries. Scampavia presents a retrospective analysis of the U.S. National Institutes of Health screening library, which fortuitously contains about 8,000 fragment-like molecules. Analysis of 200+ HTS campaigns show that these compounds behave like most others in terms of hit rate and activity. Interestingly, however, molecules that are related to these fragment-like hits show a 50x increase in hit rate compared to the remainder of the library. This work suggests that fragments should be included in diversity libraries and that selecting sub-libraries based on the activity of these fragments could be an efficient and rapid way of sampling a large compound library.

Andreas Bender
University of Cambridge, U.K.
Using Data to Decide Which Compounds to Screen: Considering Cytotoxicity in Compound Selection, and Utilizing ‘Informer Compound Sets’ and Iterative Screening to Decrease Experimental Effort and Cost

Bender has published on multiple different approaches to rational screen design, and here he talks on the theme of increasing the quality of focused library sets that can be used as starting points for rational screening strategies.

In a first study, he focuses on something to avoid in a screening collection – namely toxic compounds. Building a classifier based on screening and structural information alongside compound annotations, he has been able to predict with good precision not only the likelihood of a compound being cytotoxic or cytostatic but also the reason why.

In a second study, he looks to build a set of compounds that are able to inform the types of molecules that have a high likelihood of being active in any given assay. By analysis of the data from this ‘informer set,’ and then applying this data to subsequent rounds of compound selection, Bender shows that iterative screening can be a fast and cost-efficient way to find the best lead molecules.   


“Coming up with the best screening strategy for a given campaign should be of interest to a broad range of people,” says Ainscow. “On one side, I hope that this will be of interest to people involved in complex assay development so that they can get a feel for how the screeners are going to handle their ‘low-throughput’ assays. On the other side, informaticians should attend to see how the tools they are developing are being used to address real world problems. Of course, the people in the middle, those actively involved in hit and lead identification, should attend to learn from case studies of how their peers are handling issues that they are most likely facing right now."

About the Author

The Lab Man is SLAS Education Director Steve Hamilton, Ph.D. He is a creative change maker, delivering the fresh thinking and energy that has helped make SLAS the go-to resource for those in life sciences R&D and technology. After years in the drug discovery world, heading many leading-edge automation projects for companies such as Eli Lilly, Scitec and Amgen, Hamilton joined the SLAS professional team in 2010. He received his Ph.D. in analytical chemistry from Purdue University and a B.S. in chemistry from Southeast Missouri State University.

October 24, 2016