Nanocyclix: next generation kinase therapeutics A chemocentric approach for the discovery of selective kinase inhibitors

Authors: Nicolas GEORGE, Pascal BENDERITTER, Petra BLOM, Marie-Hélène FOUCHET, Alexis DENIS and Jan HOFLACK

Abstract: Our kinase focused library of small macrocycles so called Nanocyclix is designed in a chemocentric approach to identify attractive and selective kinase inhibitors across the kinome. All compounds are in the drug-like properties space and hit compounds display nM potencies and good selectivity against a small number of kinases. Nanocyclix® Oncodesign’s proprietary medicinal chemistry technology is used in its drug discovery programs. Conceptually, the Nanocyclix® technology is based on the macrocyclization paradigm of known hinge binder scaffolds resulting in tighter binding site recognition, potency and selectivity towards the ATP site. Exploring different lengths and functionalities of the cyclic linker allows to populate the conformational space of every template and to identify an optimal match between the size and mobility of the binding site and the macrocyclic ligand. Extensive profiling of the full Nanocyclix collection allows selecting and valorizing the most attractive compounds and scaffold-linker combinations at an early stage. Typically, Nanocyclix are profiled against broad panel of kinases in biochemical assays and eADMET parameters.

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