Subventions et des contributions :

Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier (2017-2018 à 2018-2019).

Proteolysis-Targeting Chimeras (PROTACs) are bifunctional molecules that allow the elimination of targetx000D
proteins --possibly responsible for various diseases-- by harnessing and bringing in a close range a ligasex000D
already present in the cells and triggering the proteolysis mechanism. Those synthetic entities are composed ofx000D
3 main parts: a scaffold that is selective for the target in one end; a scaffold that is selective for the E3 ligase onx000D
the other end; and a linker that binds them together. Since 2008, new generations of PROTACs based on smallx000D
molecule moieties have been developed, contrasting with earlier systems using large peptidic motifs andx000D
presenting several issues, notably their solubility and cell permeability.x000D
Despite their advantages of this early field, the area of small molecules PROTACs presents some drawbacksx000D
and gray areas. Firstly, their syntheses can be long and tedious, especially concerning the central linker.x000D
Secondly, the variety of those linkers is quite scarce, as poly-ether or alkyl chains are almost exclusively used.x000D
Thirdly, their length variation and effects on the activity of the PROTACs are rarely studied.x000D
The goals of this project are to: 1) develop new synthetic routes allowing the easier synthesis of various linkersx000D
using up-to-date technologies, such as automated supported synthesis, solid and soluble supports or flowx000D
chemistry; 2) develop new categories of linkers that will be tested for activity using standard POI and E3 ligasex000D
ligands; 3) combine those advances to allow the rapid synthesis of a wide range of linkers that will constitute ax000D
toolbox for next generation PROTACs.