March 12, 2019

From target discovery through launching a finished product to market, developing a new drug is a complex process which takes on average 10-15 years and costs around 2.6 billion dollars.

Early on, this process often involves a high-throughput screening (HTS) campaign in order to identify high-quality, innovative compounds for research, and ultimately clinical development. For every drug that makes it to market, 10,000+ compounds are synthesized and evaluated. Because these programs require significant investment, the availability of an innovative, relevant and high-quality compound collection for screening is critical. Testing high-quality screening collections will pay substantial dividends down the line – essentially, having the best compounds to start with gives the best chance of long term success.

There are a number of challenges facing small molecule screening programs which were highlighted in our recent webinar by Michael P. Trova, Ph.D., Senior Vice President of Drug Discovery at AMRI. The chemical space available to be sampled in research programs is vast and sparsely populated, meaning significant resources need to be invested to generate and maintain a competitive compound collection. New screening technologies are creating not only opportunities but challenges as well, such as phenotypic HTS using high-content imaging, which allows access to new biological targets, and label-free technology, which identifies higher fidelity lead compounds. Both of these screening technologies require a high-quality screening collection. Furthermore, there are a number of “undruggable” targets for which identification of hit compounds are challenging, as investigators are also often using outdated screening collections which cover a limited amount of chemical space, much of which is well-studied and evaluated, resulting in a weak IP position, and making it hard to advance the leads they provide.

There is also the economics of increasing chemical diversity to consider – the more compounds screened, the greater the cost. For that reason, it is crucial that only high-quality compounds are screened, so each testing point provides valuable insight and information. Put simply, just because it is possible to screen millions of compounds, that isn’t necessarily best practice.

So what are some ideal characteristics of a high-quality compound screening collection and solutions to the challenges faced by the industry? According to Trova, unique compounds will provide medicinal chemists with a proprietary starting point for investigations. Part of that is having access to exclusive or semi-exclusive screening compounds that help avoid competitive and IP issues. What’s more, the application of computational library design principles will result in libraries which are more relevant to testing, and certainly, the application of new synthetic chemistry will provide high quality and diverse screening libraries. Trova also insists that the purity of the compounds should be very high, and there should be a focus on compound design quality rather than the total number of compounds (as previously mentioned). While a large number (500,000+) of compounds should be screened, it is also important that the compounds are structurally diverse, i.e., composed of fragments, scaffolds, hit-like, lead-like, and drug-like final compounds.

AMRI’s approach to synthesizing compound screening collections is to address challenges faced by the industry by leveraging its synthetic and medicinal chemistry expertise. As a result, AMRI has created a series of unique, high-purity, cost-effective, small molecule synthetic compound libraries designed for screening and hit-to-lead programs. In particular, this webinar discussed AMRI’s novel Compound Library Consortium (CLC).

Rather than producing large numbers of compounds via an unselective approach, the AMRI-led CLC focuses on designing novel, core scaffolds and templates, and then synthesizing ca. 200 compounds per scaffold, purifying them to greater than 90 percent before delivery. Screening compounds are selected for synthesis by designing small changes in the chemical structure that potentially affect its physicochemical properties, toxicology, potency, and binding interactions — all key elements in finding a compound with the best chance of providing quality leads suitable for lead optimization activities.

The CLC prepared and delivered 70,000 compounds over two years, with its members also benefiting from shared costs, semi-exclusivity and economies of scales, as well as shared best practices and innovation.

Following on from the success of the CLC, AMRI is launching CLC II to create a next generation, semi-exclusive set of compounds for drug discovery. For further information on how to get involved with this unique program, please contact us.

For more information on anything discussed in this article, please access the full webinar here.

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