Drug Targets Historical Perspectives

Drugs are natural or designed substances used deliberately to produce pharmacological effects in humans or animals. Drugs have been part of human civilizations for millennia. However, until the very recent modern era, drugs have been introduced to humans by empiricism and largely by serendipitous events such as encounters with natural products in search of food or by avoiding hazardous plants and animal products. The emergence of the scientific era in drug discovery evolved alongside the emergence of physical and chemical sciences at large, first as knowledge to distill, isolate, and enrich the desired substance from its natural environment, followed by deliberate attempts to modify natural substances to better serve the human needs and desires.

Scientific evolution throughout the past two centuries enabled identification of biologically active substances in humans (e.g., hormones) which were

Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy, Edited by Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari Copyright © 2010 John Wiley & Sons, Inc.

manipulated chemically to improve (potency, duration of action, and exposure), or to mitigate or abrogate undesirable actions. The cumulative knowledge of human, animal, and plant biology and chemistry provided the scientific foundation and technical capabilities to alter natural substances purposely in order to improve them. Such evolution marked the era of forward pharmacology. The era of forward pharmacology is about drug design that emanates from primary knowledge of the action of the biological target that has clear biological action.

The exponential progress in molecular biology since the mid-twentieth century, culminating in deciphering the complete human genome in the year 2000, brought the dawn of pharmacogenomics and the reverse pharmacology era. The reverse pharmacology era is defined by the need, first, to clarify the biology and medical perspectives of the target so as to qualify it as a drugable and pharmaceutically exploitable for drug discovery and development scheme. The pharmacogenomic era provides vast opportunities for selection of new molecular targets from a gamut of approximately 30,000 primary genes, over 100,000 proteins, and multiples of their translational and metabolomics products. Thus, the permutations in respect to opportunities for pharmacological interventions are unprecedented, vast, and most promising for innovative medicines.

The pharmacogenomics era as a source for drug targets also poses unprecedented hurdles in selection, validation, and translation into effective and safe drugs. New technologies continue to drive efficiency and robustness of mining the genomic drug discovery opportunities, but physiological and integrated biology knowledge is lagging. In this perspective, translational medicine and biomarkers research have taken center stage in validation of the molecular target for pharmaceutical exploitation.

In this chapter we offer a utilitarian approach to biomarkers and target selection and validation that is driven by the translational medicine prospect of the target to become a successful drug target. We hereby offer classification and analytical process aimed to assess risk, innovation, feasibility, and predictability of success of translating novel targets into successful drugs. We provide clear definitions of the type of biomarkers that are the core of translational medicine and biomarkers research in modern pharmaceutical companies.

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Project Management Made Easy

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