Current Pharmaceutical Biotechnology - Volume 11, Issue 7, 2010

The inter-discplinary science of Drug and Lead discovery continues to evolve and it does so by bringing more technologies to the lab. In the last decade we saw the advent of technologies that change the way we approach target biology (the human genome project), build compound collections (combinatorial, automated and contract synthesis), conduct screening (high throughput and high content screens), and ultimately advance compounds from discovery to development. While the rate of NMEs is constant or even down, the “easy targets”, clearly a qualitative term, are done. Now we are faced with solving the challenges of hard targets. In the next decade we will see more technology driven advances as we continue to put safe and efficacious medicines in the market. What are these new technologies and approaches? A few of them are high-lighted in this special issue of Current Pharmaceutical Biotechnology. First, David Dunn et al. discuss systems biology in “Taking a systems approach to the discovery of novel therapeutic targets and biomarkers”. Systems biology focuses on the integrated roles of cellular pathways and networks rather than single biomolecules as we have done previously. A systems biology approach requires technology that can generate and analyze, large multi-dimensional data sets. Changes in phenotype are evaluated in high content phenotypic screens, and changes in transcriptional and protein networks are evaluated against collections of small molecules, peptides or siRNA to identify agents that modulate the cellular phenotypic signatures. Such agents can be used to analyze pathways and networks. The power of this technology is its ability to generate patterns of complex biological data. These patterns can then identify new pathways and targets that are relevant to drug discovery. Next, Attila Seyhan et al. have contributed a critical discussion on “RNAi screening for the discovery of novel modulators in human disease”. RNA interference (RNAi)-mediated gene inhibition allows for systematic loss-of-function screens to be conducted to interrogate the biological functions of specific genes and pathways. The use of RNAi in various screening formats and against various targets is discussed. In addition to finding new targets and cellular pathways and networks, we discuss new twists to screen old targets. Jim Beasley and Robert Swanson have contributed a paper on sophisticated counter-screening in “Pathway-specific, species, and sub-type counter-screening for better GPCR hits in HTS”. GPCRs are well-trodden targets with great success as medicines, but some notable failures as well. Time and cost may be saved if GPCR modulators are assessed in terms of signaling pathway selectivity, species selectivity, and selectivity against closely-related family members at the stage of high-throughput screening. Examples of how these kinds of selectivity have been addressed during screening are given. In the realm of academic based screening, Rathnum Chagaturu et al. discuss the progress and challenges of academic screening in “Open access high throughput drug discovery in the public domain: A mount everest in the making”. In the current drug discovery landscape, the pharmaceutical industry is embracing strategies with academia to maximize their research capabilities and feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain. The various facets of academic HTS centers as well as the implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. Where do all of these new technological approaches to targets and screening take us? To the interrogation of a target through medicinal chemistry. To be sure, chemistry is advancing as well and Suresh Tice and his colleague discuss “Structure based design of 11b-HSD1 inhibitors”. Controlling elevated tissue-specific levels of cortisol is a novel therapeutic approach for treating metabolic syndrome. Medicinal chemistry efforts to design of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors have been aided by high resolution X-ray crystal structures of inhibitors in complex with the enzyme. Diverse classes of molecules, binding modes, structure-activity relationships, and pharmacodynamic data of such inhibitors is presented.

Systems biology focuses on the roles of cellular pathways and networks rather than single biomolecules to describe biological function. A systems view of biology requires technology that can generate and quantitatively analyze, large multi-dimensional data sets from many different sources. New technology has made this approach to drug discovery increasingly feasible. Detailed changes in cellular phenotype can be quantitatively measured using high content phenotypic screens. Changes in a cells entire transcriptome or proteome can be profiled in detail. Libraries of small molecules, peptides or poly-nucleotides such as siRNA can be screened to identify perturbagens that modulate transcriptomic, proteomic and cellular phenotypic signatures. These molecular agents can be used to deconvolute pathways and networks. The power of these technologies lies in their ability to generate complex biological data at massive scales. Integration and analysis of this multi-parametric data is vital to systems biology research. Patterns and relationships within these data sets can be revealed using factor and principal component analysis. These patterns can point to pathways that are relevant to specific biological processes making the ultimate goal of understanding the biology of a cell at the systems level possible.

The development of RNA interference (RNAi)-mediated gene inhibition has changed the direction and speed of drug target discovery and validation. RNAi technology has already influenced strategies for the pharmacological treatment of many diseases including cancer, viral diseases, bacterial pathogens, inflammation, diseases of central nervous systems (CNS), and others. This technology provides a better understanding of the mechanisms which underlie disease pathogenesis and lead to the identification of novel factors that alter the disease phenotype. With the introduction of RNAi libraries in various formats, systematic loss-of-function screens can now be conducted to interrogate the biological functions of specific genes and pathways or an entire genome in various disease areas. The identification of novel mediators of cellular response to disease pathogenesis or treatment approaches may lead to the identification of novel drug targets, development of combinatorial treatment approaches, or pharmacodynamic and patient selection biomarkers and expand our understanding of disease pathogenesis. Here, we review the use of RNAi in various screening formats, and examine the types of targets pursued for oncology and other disease indications.

G protein-coupled receptors represent one of the largest families of drug targets. Time and cost may be saved if GPCR modulators are assessed in terms of signaling pathway selectivity, species selectivity, and selectivity against closely-related family members early in the drug discovery process, perhaps even at the stage of high-throughput screening. Examples are given of how these kinds of selectivity have been addressed during screening.

High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry's best practices for a successful outcome.

Controlling elevated tissue-specific levels of cortisol may provide a novel therapeutic approach for treating metabolic syndrome. This concept has spurred large scale medicinal chemistry efforts in the pharmaceutical industry for the design of 11β-HSD1 inhibitors. High resolution X-ray crystal structures of inhibitors in complex with the enzyme have facilitated the structure-based design of diverse classes of molecules. A summary of binding modes, trends in structure- activity relationships, and the pharmacodynamic data of inhibitors from each class is presented.