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

蛋白水解靶向嵌合体（PROTAC）是双功能分子，其通过利用和引入已经存在于细胞中的近距离连接酶并触发蛋白水解机制来消除靶蛋白-可能导致各种疾病。这些合成实体由3个主要部分组成：一端对靶点具有选择性的支架;另一端对E3连接酶具有选择性的支架;以及将它们结合在一起的接头。自2008年以来，基于小分子的新一代PROTAC已经开发出来，与使用大肽基序的早期系统相比，存在一些问题，特别是它们的溶解性和细胞渗透性。尽管小分子PROTAC在这一早期领域具有优势，但仍存在一些缺点和灰色区域。首先，它们的合成可能是漫长而繁琐的，特别是关于中心连接体;其次，这些连接体的种类相当稀少，因为几乎只使用聚醚或烷基链;第三，它们的长度变化和对PROTAC活性的影响很少研究。本项目的目标是：1）开发新的合成路线，允许使用最新技术更容易地合成各种接头，例如自动化支持合成，固体和可溶性支持或流动化学; 2）开发新类别的接头，其将使用标准POI和E3连接配体测试活性; 3）联合收割机结合这些进展以允许快速合成将构成下一代PROTAC的工具箱的广泛的接头。

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.