Molecular Drug Targets and Drug Delivery

Introduction

Targeted Precision Drugs

The term “targeted drugs” has been used broadly to describe drugs that act on general pathways that have been found to be associated with disease (but that also remains functional in normal cells), but it has also been used to refer to drugs approved for a selected and limited “target” population. In here, our interest focuses on drugs that interact specifically with a molecular structure, i.e., its target that has been clearly identified and validated as being uniquely associated with a given disease;

therapeutic antibodies are probably the best example of targeted drugs. Oncology is a therapeutic area that illustrates well the challenges in defining efficacy targets. According to the NIH National Cancer Institute [1] there are many different targeted therapies that have been approved for use in cancer treatment. These include hormone therapies that slow or stop the growth of hormone-sensitive tumors, signal transduction inhibitors that interrupt communications between a cell and its environment, gene expression modulators that modify the function of proteins that are involved in the process of gene expression, apoptosis inducers, angiogenesis inhibitors, and others. Most of these do not act solely on specific molecular targets of the disease as defined in the previous paragraph. A landscape of molecular drug targets has been comprehensively discussed recently by Santos, et al. [2]. The authors examined a total of 893 human and pathogen-derived biomolecules that have so far formed a basis for 1,578 US FDA-approved drugs. These biomolecules include 667 human-genome-derived proteins targeted by drugs for human disease. It would seem that there is enough basic material on which to Open Access Journal of Cancer & Oncology

develop targeted drugs until the PMI generates new actionable information. So how can this information be used to develop site / cell-specific drugs? Korcsmaros, et al. [3] reported that “despite improved rational drug design and a remarkable progress in genomic, proteomic and high-throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade”.

Development of Targeted Precision Drugs

Validation techniques used include in vitro tools, the use of whole animal models to establish safety and efficacy (phenotypic screening, gene association studies, chemo proteomics, transgenetic organisms, imaging, biomarkers, etc.) ultimately aiming to modulate the desired target in disease patients. The conventional process of selecting new compounds as drug candidates has been using solubility and permeability assessments to evaluate the potential of a compound to be a drug. The reason is that in the conventional process of drug development, solubility plays a critical role in drug’s bioavailability (e.g., access to a patient's circulation, absorption from the digestive

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There have always been many failures in the process of drug discovery and development, for a number of reasons. One of the reasons is surely our lack of understanding of the underlying causes or pathways of a disease. Developing drugs for Alzheimer’s can be used as an illustration – to date, “promising” biomarkers (such as amyloid plaque), when tested, have all failed to predict clinical improvement. Defining whether a drug is “targeted” should be based on data. The FDA categorizes anti-cancer approved drugs into three categories – a) cytotoxic agents that act on human DNA and/or RNA, b) cytotoxic agents that act at least partially through protein targets, and c) drugs that the FDA considers to be “targeted therapeutics” [1]. However, the actual assignment of a drug to the third group rather than the second group is complicated by the broad spectrum of targeting observed. Many of the drugs (such as topoisomerase inhibitors) are selective for their targets but are highly toxic. Some kinase inhibitors show a wide range of normally functioning kinases and their associated pathways, but also adverse reactions. Classifying drugs as being “targeted” to their structural focus of biological activity when the therapeutic activity of the drug is accompanied by side effects is highly questionable. Target definition is likely to become even more difficult in case of genetic variations in order to characterize clinical efficacy and safety, and predict drug utility in individual patients or in patient subgroups.

Future Challenges

PMI is likely to add information about the causes of complex disease. Considering that disease conditions may arise from a combination of environmental factors, genetic and epigenetic dysfunction, our true understanding of disease may not become any clearer. Given such complexity, will the relative “simplicity” of targeted drug delivery, targeted therapy and precision drugs actually work? Thus, will a reductionist approach to targeted therapy still have a role in the future? Some argue that “an armory of mechanistically sophisticated and thoroughly experimentally annotated drugs that target this complexity is required”, and envisage a role for drug combinations, network drugs [7] and “polypharmacology” [8]. To quote Aristotle: “The more you know, the more you know you don't know.” So, it is quite conceivable that the “ideal”, “perfect” precision drug as we would like to see it – with very high target selectivity, high efficacy and no side effects will remain in the land of Utopia.

It has been long recognized that an important part of drug discovery is serendipity. Developing targeted drugs should be a less unpredictable process as it should, and can be based on a more extensive, validated information, derived from new insights into disease and fundamental biology that are emerging, understanding of the associations between currently successful drugs, their efficacy targets, phenotypic effects and disease indications that have been reported [1]. All this should aid efficient discovery of a new generation of medicines. Selected drug targets should have a critical role in the disease process with less significant involvement in other important processes to limit potential side-effects, have an expression pattern allowing for drug efficacy by, for example showing tissue-specific expression, and have structural and functional properties allowing for drug specificity. Two directions for developing “precision drug” would seem to emerge from the above considerations: 1. Developing molecular structures that bind uniquely to targets that have been validated to be associated solely with molecular targets of the disease origin, progression, or elimination. These are likely to be small molecules with an ability to reach the targets in various locations of the body. In this case, there may not be any need to employ drug carriers; an optimal formulation should suffice. 2. Genetic material needs to enter cells to interact with its intra-cellular target. In most cases it cannot do it by itself, (but naked DNA can be made to enter cells using electric current – i.e., by electroporation [9]) and hence a carrier needs to be employed. Carriers most commonly used in gene therapy are viruses, liposomes and nanoparticles. Clearly, vehicles to deliver genes must be able to recognize and deliver their “pay load” to specific cell types. However, none of the vehicles has so far been found entirely satisfactory. Currently, there are 3541 genes listed in the UniProt database for which there is experimental evidence that the genes are involved in various disease conditions, including cancer, neurologic, systemic and cardiovascular disease. Some 1129 of these have been deemed as being of possible interest as potential drug targets because they belong to known drug-target protein classes i.e., enzymes, transporters, receptors and ion-channels, and as such have not yet been targets for FDA approved or experimental drugs [10, 11].

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Conclusion

It is apparent that there is no need to wait for the efforts of the PMI to produce new knowledge and new data. There is enough known for us to start working towards generating precision drugs. The past failures need to be recognized, avoided, and built on.