Scientific Publication Macrocyclisation process

Abstract "Nanocyclix®: a chemocentric approach for the discovery of selective kinase inhibitors"

Petra BLOM, Pascal BENDERITTER, Nicolas GEORGE, Marie-Hélène FOUCHET, Alexis DENIS, Jan HOFLACK & Philippe GENNE

Macrocycles have been emerging as a valuable class of pharmacological agents over the past decade. A growing appreciation of potent and selective protein-ligand interactions, which are not easily addressed using small molecules, calls for the development of inhibitors that are more sophisticated than traditional open form, non-macrocyclic small molecules. Macrocyclic kinase inhibitors have reached advanced clinical testing and are having a significant impact in different disease areas such as oncology and inflammation. The number of reports of innovative macrocycles in preclinical research is continuously increasing in literature.

At Oncodesign, macrocyclisation is systematically applied within all projects leading to a Nanocyclix® platform. Restriction of the conformational freedom in small molecules can result in high affinity and selectivity for various classes of biological targets such as, but not only, kinases. Bioactive Nanocyclix® are designed with the goal of pre-organizing their three dimensional shape into a well-defined conformation. The rationale is to diminish entropic penalties in the course of a protein/ligand interaction, which occur between the proteins active pocket and the macrocyclic ligand. The conformational rigidity also results in a high degree of specificity, not only between target classes, but also in a very high degree of selectivity within a target class such as kinases and even within closely related sub kinase families (wild-type forms and/or mutants). This high degree of selectivity is based on three dimensional shape complementarity between the kinases active pocket and the Nanocyclix® ligand.

Nanocyclix processNanocyclix Process

The Nanocyclix® chemistry technology comprises the generation of compounds through a macrocylization process which results in small, low MW kinase inhibitors with a unique binding mode and mode of action compared to the open form kinase inhibitors. Not only the Nanocyclix® technology is used in the search for therapeutically active agents, but also in the identification of novel, clinically relevant PET tracers.
In this presentation, we describe the Nanocyclix® platform, characteristics of the technology, applied medicinal chemistry approaches as well as examples in different projects.

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