Efficient Synthesis of a PROTAC Library Using Supported Chemistry and Automated/Continuous Flow Technologies

点击翻译按钮获取中文摘要

Proteolysis-Targeting Chimeras (PROTACs) are bifunctional molecules that allow the elimination of targetproteins --possibly responsible for various diseases-- by harnessing and bringing in a close range a ligasealready present in the cells and triggering the proteolysis mechanism. Those synthetic entities are composed of3 main parts: a scaffold that is selective for the target in one end; a scaffold that is selective for the E3 ligase onthe other end; and a linker that binds them together. Since 2008, new generations of PROTACs based on smallmolecule moieties have been developed, contrasting with earlier systems using large peptidic motifs andpresenting several issues, notably their solubility and cell permeability.Despite their advantages of this early field, the area of small molecules PROTACs presents some drawbacksand gray areas. Firstly, their syntheses can be long and tedious, especially concerning the central linker.Secondly, the variety of those linkers is quite scarce, as poly-ether or alkyl chains are almost exclusively used.Thirdly, their length variation and effects on the activity of the PROTACs are rarely studied.The goals of this project are to: 1) develop new synthetic routes allowing the easier synthesis of various linkersusing up-to-date technologies, such as automated supported synthesis, solid and soluble supports or flowchemistry; 2) develop new categories of linkers that will be tested for activity using standard POI and E3 ligaseligands; 3) combine those advances to allow the rapid synthesis of a wide range of linkers that will constitute atoolbox for next generation PROTACs.