Polypharmacology: targeted approach as a rocket science

Targeted approach has shown its inefficiency in a majority of fields – this is a factum. This paradigm is still very popular due to it is very primitive and mechanistic. It is intuitively understandable for everybody and cannot be simply changed. But how to explain the fact that it should work as if it were correct? Here is an example of an attempt of such an explanation. Just several quotes:

In theory, the large amount of data obtained on drug action, metabolism, safety and efficacy in preclinical studies, as well as in phase I and II clinical trials, should ensure a high success rate in phase III trials. However, many drugs fail at the phase III stage, primarily because of a lack of efficacy (ie, no significant difference between placebo and drug treatment, or between the investigational drug and current treatment alternatives). The risk of failure is higher if the drug has a novel mechanism of action (ie, a newly identified target). This problematic evidence indicates that new approaches are necessary in drug-discovery strategies.

Defining the complex mechanisms underlying diseases is challenging. The viewpoint that diseases can be understood by a Mendelian perspective, or the ‘one gene-one disease’ theory, and treated with a ‘magic–bullet’ therapy, has proven to be unsuccessful. Many diseases are not associated with a single genetic determinant. Instead, a complex multiplicity of genetic determinants leads to a disease state, and a single genetic determinant can influence more than one disease. In addition, environmental factors, tissue type, hormone levels and age play a role in how genetic determinants dictate disease manifestation. This complexity in disease origins arises because the impact on protein function or expression level is controlled by the regulatory network within which a protein exists.

In order to gain a systems-level perspective of disease at the molecular level, a systems view of the relevant physiological function is essential. Each physiological process has an underlying signaling network of chemicals, hormones, protein receptors, ligands, enzymes, transcription factors, ions or DNA/RNA that modulate biochemical reactions, electrical signals, mRNA transcription and protein translation. These reactions can each occur with different kinetics, and simultaneously and/or at different time points, as well as at varying levels of magnitude. Therefore, each physiological function or phenotype is controlled by a complicated network of signals.

Sure, we understand the complexity. But what is the proposal of the author? Guess what? Just to dig even deeper!

Therapeutic polypharmacology includes the concept of treating multigenic, complex diseases by targeting multiple targets with one or more drugs, in order to effectively reset the regulatory network processes that are altered in the disease state. Adverse polypharmacology comprises the scenarios in which the ‘offtarget’ binding of drugs leads to adverse effects. Such interactions include binding to protein targets other than the therapeutic target and binding to the therapeutic target in non-target tissue.

The systematic treatment of a single disease at two or more targets (ie, critical nodes) requires a combination of the empirical knowledge of which drugs are effective against each pathophysiology and the knowledge gained from a systems approach to understanding how multiple nodes cooperate in a signaling network to produce the pathophysiology associated with the disease. Ideally, each disease would be treated by therapeutic polypharmacology – the combination of ‘targeted therapies’ that modulate multiple, specific signaling components or interactions that malfunction in a given disease. The regulatory network surrounding the drug targets and/or disease would be analyzed, accounting for the modulations resulting from the targeted therapy treatment. Combining the building of interaction networks for various diseases with genome-wide analyses of changes, such as SNPs or copy-number variations, will allow a significant expansion of the list of possible drug targets in a physiologically relevant manner. Each gene product associated with disease is not necessarily ‘druggable’; however, an analysis of the druggability of the human genome, according to the structural and functional properties of each protein, supports the view that the current ‘drugome’ can be greatly expanded and diversified.

As I understood if the targeted approach failed we have to replace it to more complicated and therefore sexier more attractive multitargeted polypharmacological approach? Well, it can help to survive the current targeted approach a couple of decades…