Introduction

The screening of chemical compounds for pharmacological activity has been ongoing in various forms for at least 40 years. The screening paradigm says that when a compound interacts with a target in a productive way, that compound then passes the first milestone on the way to becoming a drug. Compounds that fail this initial screen go back into the library, perhaps to be screened later against other targets.

The perceived needs of the pharmaceutical industry have changed with time and driven marked changes in the industry, both in terms of its business structures and its scientific approaches to drug discovery and development. In response, screening methodologies have also improved with time, both in terms of throughput and the amount of information to be derived from the screen. Advances in assay and instrument technologies have provided the means necessary to address these evolving needs.

Elements of High-Throughput Screening Technology

High-throughput screening is a key link in the chain comprising the industrialized drug discovery paradigm. Today, many pharmaceutical companies are screening 100,000–300,000 or more compounds per screen to produce approximately 100–300 hits. On average, one or two of these become lead compound series. Larger screens of up to 1,000,000 compounds in several months may be required to generate something closer to five leads. Improvements in lead generation can also come from optimizing library diversity. Limited success has been achieved to date in this realm.

High-throughput screening is perhaps most accurately understood as one stage in an evolving process. Since the 1980s, improvements in screening technologies have resulted in throughputs that have increased from 10,000 assays per year to current levels, which can approach ultrahigh-throughput screening levels of more than 100,000 assays per day. High-throughput screening is evolving not only as a discrete activity, but as a perspective that is expanding backward toward target identification and validation and forward to converting assay hits to qualified leads via information generated either within screens or through downstream, high-throughput ADME (absorption, distribution, metabolism, and excretion) and toxicity testing.

In terms of definition, high-throughput screening can be considered the process in which batches of compounds are tested for binding activity or biological activity against target molecules. Test compounds act as inhibitors of target enzymes, as competitors for binding of a natural ligand to its receptor, as agonists or antagonists for receptor-mediated intracellular processes, and so forth. High-throughput screening seeks to screen large numbers of compounds rapidly and in parallel. Yet in another sense, high-throughput screening is an evolving process that is today a discrete activity and may tomorrow become more highly integrated into a rapidly changing drug discovery paradigm.

Positive high-throughput screening results are usually called hits. Compounds resulting in hits are collected for further testing in which, for example, the potency of an enzyme inhibitor or the binding affinity of a ligand for a receptor may be determined. After this second level of triage, hits become lead compounds. Further synthesis may then be required to provide a variety of compounds structurally related to the lead. These sublibraries must then be screened against targets in order to choose optimal structures. At this stage, some basic indicators of toxicity or bioavailability may be considered in an attempt to eliminate potential failures as early in the discovery process as possible.

Market and Technology Factors Underlying High-Throughput Screening

High-throughput screening was formed from a confluence of market-driven needs within the pharmaceutical industry and technological strategies originated within the in vitro diagnostics industry. A convergence of several trends is promising to yield a highly effective new paradigm for drug discovery. While the exact nature of the new paradigm is not yet clear, its outlines are starting to emerge from the mist. Trends include: the influence of genomics on increasing both the quantity and quality of new drug targets; advances in combinatorial organic synthesis to increase both the quantity and quality of compound libraries; the influence of high-throughput screening in providing an increased supply of new lead compounds; and the enhanced use of bioinformatics for process integration.

The pharmaceutical industry currently has a pressing need for improvement in high-throughput screening technology. Although the industry has a seemingly insatiable appetite for new lead compounds, it is also under continuing pressure to reduce the costs of discovery and development. Historically, the industry has shown its enormous potential both for the improvement of human health and the realization of significant profits in that process. Over the past three decades, this potential has propelled rapid advancement both in the valuation of large pharmaceutical companies and in the basic sciences that provide them with their technical foundation.

In the last half of the current decade, high-throughput screening instruments, assays, and services have emerged as a significant growth market. From the field’s origins with home-brew tests and generic research instrumentation, high-throughput screening has become an increasingly sophisticated and important element in the armamentarium of the drug discoverer. The discovery process is currently on a steep growth curve both with respect to the number of targets and compounds to be screened and the complexity of the assays required. Increased numbers of targets and compounds call for greater parallelism and/or increased throughput in screens. Furthermore, the expense and scarcity of targets and compounds have driven a trend toward smaller assay volumes through miniaturization.

Manufacturers have risen to the occasion with a plethora of new offerings, including new assays, new formats, new technologies, and new instruments. Microfluidics technologies, for example, are being applied to the development of systems that consume subnanoliter quantities of reagents. New alternative technologies and systems come at a cost, and manufacturers are continually faced with assessing their true cost-benefit ratios.

The Business of High-Throughput Screening

High-throughput screening appears at first glance to be a relatively straightforward activity, a sort of numbers game. Screening more compounds against more targets per unit time should generate more hits, which should generate more leads, which should generate more products. Some industry participants accept this view, others do not accept it all, and most offer provisos. No contemplation of high-throughput screening can be considered complete without recognition of two key factors: (1) drug discovery is in the midst of revolutionary and very rapid changes; and (2) high-throughput screening cannot be considered in isolation from other aspects of drug discovery. These considerations will shape the long-term future of high-throughput screening. For the present, however, momentum from the existing drug discovery paradigm, with its goals and limitations, will continue to have major influence over the nature of products and services. Indeed, the pharmaceutical industry is virtually forced to catch its breath and assimilate the paradigm governed by optimizing the random screening of large libraries to generate hits before it can move on the incorporate changes reflecting the integration of downstream activities into primary screens.

Pharmaceutical companies are forced to deal with several major issues that determine the scope and nature of their high-throughput screening programs. First, quantities of compounds in company libraries are often quite small. Depletion of libraries is highly problematic both because replacement is costly and in many instances extremely difficult to accomplish. Therefore, companies aim to maximize quantities of compounds in libraries and to minimize the quantities used in any given screen. A second key issue relates to the diversity of technological choices that must be made. Reduction of compound usage requires reduction of assay volumes, and such reduction can be accomplished either by reducing the size of microplate wells in the current assay paradigm or by adopting new-paradigm microfluidic and other alternative approaches. Miniaturization through high-density microtiter plates implies a shift to homogeneous assays in order to avoid the difficulties and, perhaps, the impossibility of manipulating microliter or smaller quantities of fluids for separation or washing operations. Platform companies in high-throughput screening provide instrumentation together with, in many instances, reagents and services. Business and product strategies are highly variable with areas of similarity.

The field of high-throughput screening has generated several types of strategic alliances. The technology access agreement is a common mechanism whereby a large company gets to use a new technology and participate in its late-stage development. For that privilege, the pre–commercial stage partner tries to obtain up-front payments, research and development payments, milestone payments, and royalty payments for resulting products. Many collaborations of this sort have indeed provided all or most of these kinds of payments.

The overall pattern for the industry serving pharmaceutical high-throughput screening is one of steady growth at rates exceeding pharmaceutical sales growth rates by a considerable margin. Growth rates for high-throughput screening exceed even rates of growth for pharmaceutical research and development. Even these high growth rates for screening lag behind the actual needs of the industry. Growth in high-throughput screening product and service revenues will be constrained by caps placed on pharmaceutical research and development expenditures in order to maintain acceptable profit margins. The revenue growth rates reflect a balance between burgeoning opportunity and the realities of spending constraints. The pharmaceutical industry is challenged to increase its output of innovative new drugs while maintaining profit levels that are acceptable to the investment community.

The Future of High-Throughput Screening

The future of high-throughput screening will be determined to a large extent by the level of funding committed to that activity by pharmaceutical companies. The levels of funding will be determined by a complex equation for optimization of the entire drug discovery process. The weighting given to the various inputs to that equation will differ among companies depending on their cultures, strategies, and the influence borne by one or another faction. A key element in such considerations is that the discovery task has shifted somewhat during the past few years from simply identifying promising leads to the added proviso that dead-end leads should be eliminated from consideration as early in the process as possible. Some inputs to the decision equation are: value received for miniaturization versus resource inputs required; the extent to which new technology provides value that extends beyond the primary screening process; the information content provided by new technology; and the technology’s “homogeneity index.” Whether a new technology or instrument is adopted will also depend on the extent to which it provides laboratory integration without destroying flexibility. Pharmaceutical companies are recognizing that their future success is tied to viewing the entire drug discovery process as a single entity.

In summary, it appears that opportunity exists for great diversity in high-throughput screening technologies and systems. The dominant theme, continual evolution, is driven by economic realities and pulled along by ever-increasing requirements for increased information content. Diversity and flexibility appear necessary, and computers will make order out of the chaos and permit creative new ways of viewing and mining data. Information systems can go far toward integrating the entire drug discovery and development process. Consequently, the modern screener must be capable of operating from multiple perspectives. Screeners must also be fluent in molecular biology, computer science, robotics, instrumentation and overall process engineering.

This article is based on the Executive Summary from D&MD Report’s “High Throughput Screening: Redefining the Mission, 2nd Edition” by Ken Rubenstein, PhD, and Cynthia Coty. For more information on this market analysis report, including how to order a copy, please click here.

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