CDithem

Consortium for Discovery and Innovation in Therapy and Medicine

  The biomedical field is under increasing pressure to accelerate the discovery and development of innovative therapeutic thus limiting the investigations to well established families of drug targets.
Indeed, the 100 best-selling drugs used worldwide target less than 50 different proteins, leaving a considerable opportunity in identifying innovative drug targets.

Most drug discovery initiatives develop and/or expand their pre-clinical and clinical pipelines focusing on G-protein coupled receptors, nuclear receptors, ion channels and enzyme active sites. While this situation is understandable for historical and risk management reasons, protein-protein interaction inhibitors represent a huge, essentially untouched diverse group of key targets for therapeutic intervention. Human life is expected to be controlled by a number of protein-protein interactions (PPI) ranging from 130,000 [1] to 650,000 [2]. Clearly, among these interactions, a sizable number of targets will be druggable with a ligandable binding pocket at the interface that could be screened using appropriate technologies and will be important for the design of tomorrow's new therapies.

In many pathological situations, small molecules able to act on protein association/dissociation would be highly desirable. In addition, such small molecules could play important roles in structure-function studies to facilitate understanding of new molecular mechanisms even if they do not become directly exploitable drug molecules to treat diseases.

The idea of inhibiting interfaces with small molecules is now the subject of numerous studies with nowadays thousands of successful compounds capable of modulating PPI targets including some drugs at clinical stages.



References


[1]
An empirical framework for binary interactome mapping.
Venkatesan, K., Rual, J.-F., Vazquez, A., Stelzl, U., Lemmens, I., Hirozane-Kishikawa, T., et al.
Nature Methods 2008, 6(1), 83-90. doi:10.1038/nmeth.1280

[2]
Estimating the size of the human interactome.
Stumpf, M. P. H., Thorne, T., de Silva, E., Stewart, R., An, H. J., Lappe, M., & Wiuf, C.
Proceedings of the National Academy of Sciences 2008, 105(19), 6959-6964. doi:10.1073/pnas.0708078105