Targets

Lets focus now on the target (Fig. 4.13). In order to have an activity, a new therapeutic must exert an action against a biological or biochemical process. As a consequence, therapeutic targets are typically enzymes, ligands, receptors, signaling molecules, or surface antigens that play a role in the biology of the disease. After an evaluation of the need for new therapeutics in a given indication, as well as the market and the potential competition, such targets are usually identified by a detailed consideration of the disease process. Importantly, throughout this process considerable attention is also placed on the intellectual property (i.e., patents) associated with the target and the therapeutic. The importance of patents and their associated know-how cannot be over stressed, as this information often forms the basis for both getting into and then surviving in the marketplace. Similarly, there may be critical intellectual property owned by others that may be essential to your product or indication. As "property," patents and know-how can be traded, bought or sold, all of which are common practice during the drug development process. Sources of new targets are identified on the slide in the four bullets.

Biotechnology particularly has focused on disease patho-physiology to uncover the secrets of human physiology and disease. Technological advances, such as in analysis of molecules and intracellular mechanisms, and whole new technologies in research methods are advancing these discoveries as well. Venture capital has been available to fund these biotech companies for these biological advances. Some examples of how biotechnology has impacted target discovery and product development are shown here (Fig. 4.14). As we have discussed, targets frequently are:

• Enzymes (aurora kinase)

• Receptors (tyrosine kinase receptors, EGFr)

• Signaling molecules (VEGF inhibitors and traps, TNF-a)

In addition to many of the existing tools, new approaches to target discovery have been identified over the last few years (Fig. 4.15) [13]. Some of these new tools are described below.

Genomics is the study of all of the nucleotide sequences, including structural genes, regulatory sequences, and noncod-ing DNA segments, in the chromosomes of an organism. When applied to target identification, genomics attempts to identify novel disease targets by comparing gene expression in normal and diseased tissues.

Proteomics is an effort to establish the identities, quantities, structures, and biochemical and cellular functions of all proteins in an organism. Said another way, proteomics attempts to understand cellular function through the measurement r Most therapeutic targets are enzymes, receptors, signaling molecules, signaling cascades or surface antigens r Initial focus is usually placed on medical need, the market, the competition, and the disease process r Considerable attention is also placed on intellectual property: C If I'm successful, can I sell my product (freedom to operate)? C If I'm successful, can I protect my product (exclusionary rights)?

r Most common sources for targets include: c In-licensing from other companies, academia or NIH o Collaboration with other companies, academia or NIH O Internal research programs C Mining published literature

Fig. 4.13. Target Identification and Selection

Targets: Company:

r IgE antibodies > Tanox / Genentech (Xolair)

r Lymphocyte CD-20 r Idec-Biogen (Rituxan)

r Tyrosine kinase receptors r Astra-Zeneca (Iressa)

- Lymphocyte CD-11a - XOMA / Genentech (Raptiva)

r Proteosome inhibitors r Millennium (Velcade)

r HIV binding and cell entry r Trimeris / Roche (Fuzeon)

k EGFR inhibitors k Imclone (Erbitux), OSI (Tarceva)

k VEGF inhibitors k Genentech (Avastin)

r VEGF receptor analogs r Regeneron (VEGF trap)

- Aurora kinase inhibitors - Vertex (VX-680)

r E2F decoy r Corgentech (Edifoligide)

r Triple serotonin MOA ► NeuroSearch (NS2359)

r Reverse lipid transport (HDL) r Esperion (ETC-216 & -588)

Fig. 4.14. Biotechnology Impact Source: Company Websites r Genomics r Proteomics r Knockout and transgenic animals r Gene silencing (antisense, siRNA) r Pharmacogenomics and single nucleotide polymorphisms r Microarrays (genes and proteins on chips) r High throughput screening r Bioinformatics r Phage (and other) display systems r New biology (e.g., protein kinases, proteosomes, apoptotic signals)

Although these new tools have increased number of potential targets, ability to generate successful therapeutics from these new targets has not (yet) significantly increased (target rich, product poor)

Fig. 4.15. New Tools of Discovery Research of protein expression, activity, and interaction with other biological macromolecules [14].

Knockout and transgenic animals are animals in which specific genes have been deleted (knockout) or inserted (transgenic), allowing a determination of the consequences (phenotypes) of either the absence or presence of the specific gene, respectively. Such information can be extremely useful confirming the value of a particular target and in designing a desired therapeutic. In fact, in a recent review [15], the phe-notypes of knockouts for targets of the 100 bestselling drugs showed good correlation with the known drug efficacy.

Gene silencing is an alternative to the creation of knockout animals, whereby double-stranded RNA (dsRNA) is able to inhibit the function of complementary single-stranded RNAs such as messenger RNA. This process, known as RNA interference (RNAi), is being widely used as a target validation tool in discovery research [16]. In addition, RNAi technologies are being explored as a means of generating new therapeutics useful against gene targets that may not be amenable to conventional therapeutics [17, 18].

Pharmacogenomics seeks to develop medicines on a personal level. It is the study of how an individual's genetic inheritance affects their response to drugs, and holds the promise that therapies might one day be selected for (or adapted to) each person's own genetic makeup. Variables such as environment, diet, age, lifestyle, and state of health all can influence each person's response to a drug. Thus, understanding an individual's genetic makeup may allow the creation of personalized drugs with greater efficacy and safety [19].

All of these tools are supported by a series of technologies (microarrays, high-throughput screening [HTS], bioinformat-ics, phage display, etc.) that can greatly facilitate the performance, evaluation, or interpretation of study results. For example, microarrays are now being used to study gene expression [20] and protein function [21], as well as to study compound toxicology [22]. The identification of new biological targets (viz., protein kinases), processes (viz., apoptosis), or structures (viz., proteosomes) has also helped focus and accelerate discovery research.

It should be emphasized, however, that all of these new tools, though they have expanded the number of potential therapeutic targets, have not yet led to the identification of successful new therapeutics. Thus, it has been said that we are currently "target rich, product poor." Because many years are required for the successful development of a new therapeutic, and because these new discovery tools have little impact on the process of drug development (purification, formulation, scale-up, manufacturing, etc.), it seems likely that the potential rapid progress touted by some for these new tools "has been greatly exaggerated." Clearly, these tools have opened up important new approaches to target and drug discovery, approaches that will most certainly have value over time.

To touch on just a few examples, here is an illustration from Nature Reviews Drug Discovery on how genomics and proteomics are being used in target identification (Fig. 4.16) [13]. For genomics, an RNA sample is amplified and labeled using the polymerase chain reaction (PCR), then used to probe gene microarray chips that contain a multitude of genes. Importantly, with the completion of the human genome project it has become possible to probe the expression of 32,000 human genes in a single experiment.

For proteomics, studies typically involve two-dimensional gel electrophoresis to separate the proteins in a sample, followed by excision from the gel and identification, frequently by mass spectroscopy. As in genomics, protein microarray techniques are also being utilized in proteomics research [23].

Globally, there are two broad approaches by which discovery tools are used to understand, identify, and then validate new targets, presented in this Nature Reviews Drug Discovery article (Fig. 4.17) [13]. The first, a molecular approach, attempts to identify new targets through an understanding of the cellular mechanisms underlying the disease. This approach is the most recent and utilizes genomic and proteomic techniques extensively.

The second approach, which has been called a systems approach, seeks to identify new targets through the study of disease in whole organisms. Throughout history, it has been the systems approach to drug development that has been the most commonly used and is particularly relevant for diseases where the observable effects can only be detected in live animals.

Importantly, there are differences in the nature of the targets identified by these approaches, as well in the types of clinical indications they can address. In terms of targets, the molecular approach is more likely to identify intracellular molecules (regulatory, structural or metabolic proteins, etc.) and has been extensively used in the investigation of oncology. Alternatively, the systems approach has been used with a broad range of indications, including obesity, atherosclerosis, heart failure, and stroke, and has identified both intracellular and extracellular targets. Even now, however, application of the molecular approach to these and other disease indications is expected to yield new therapeutic approaches.

Fig. 4.16. Examples of Tools (Adapted with permission from Nature Publishing Group. London, England. From Figure in Lindsay MA. Nature Reviews Drug Discovery 2003; 2(10):831. Figure - Target discovery)

Fig. 4.16. Examples of Tools (Adapted with permission from Nature Publishing Group. London, England. From Figure in Lindsay MA. Nature Reviews Drug Discovery 2003; 2(10):831. Figure - Target discovery)

Fig. 4.17. How these tools fit together (Adapted with permission from Nature Publishing Group. London, England. From Figure in Lindsay MA. Nature Reviews Drug Discovery 2003; 2(10):831. Figure - Target discovery)

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