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

蛋白水解靶向嵌合体(PROTAC)是一种双功能分子，通过利用和近距离利用细胞中已存在的连接酶并触发蛋白降解机制，可以消除可能导致各种疾病的目标蛋白。这些合成实体由3个主要部分组成：一端对靶标具有选择性的支架；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连接物。自2008年以来，基于小分子部分的新一代PROTAC已经被开发出来，与使用大分子基序的早期系统相比，出现了几个问题，特别是它们的溶解性和细胞渗透性。尽管小分子PROTAC具有这一早期领域的优势，但小分子PROTAC领域存在一些缺陷和灰色区域。首先，它们的合成可能是冗长和繁琐的，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活性的影响很少被研究。本项目的目标是：1)开发新的合成路线，允许使用最新的技术，如自动支持的合成，固体和可溶性载体或流动化学，更容易地合成各种连接体；2)开发新的连接体类别，将使用标准的POI和E3配体进行活性测试；3)结合这些进展，允许快速合成各种连接体，这些连接体将构成下一代PROTAC的Toolbox。

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.