IAPs是近10年来新药研发的重要靶点，迄今已有多个小分子IAPs抑制剂进入临床研究。目前发现的小分子IAPs抑制剂主要有两类，一类是单体，可以模拟Smac氮端的四肽AVPI与这些IAPs中的BIR3结合，但不能与XIAP的BIR2有效结合；另一类是带有两个模拟AVPI的结构单元的二聚体，可以同时跟XIAP的BIR2和BIR3结合。选择性作用于XIAP和其它IAPs的BIR2的小分子化合物的研究还处于早期。本项目中设计了一类新的BIR2选择性的XIAP抑制剂，并提出了有效的合成方法。基于这类化合物，本项目中还提出了设计与合成新型二聚体IAPs抑制剂和新型的诱导靶蛋白泛素化的PROTACs探针的方法，并将对这些化合物的作用机制进行研究。本项目的成功实施，有可能发现新的用于临床研究的小分子IAPs抑制剂。

IAPs are attractive targets in drug development in the last ten years. Currently multiple small molecular inhibitors of IAPs have entered clinical developments. Two types of IAPs inhibitors have been developed, one type is monomer which mimics AVPI, the N terminal four mer peptide of Smac by targeting the BIR3 domain of these IAPs, but this type of compounds are unable to potently bind to the BIR2 domain of XIAP. Another one is dimmer which can concurrently bind to both the BIR2 and BIR3 domains of XIAP and efficiently antagonize both XIAP and cIAP1/2. The study for small molecular compounds selectively targeting the BIR2 domain of XIAP and other IAPs is in its early stage. In this project we proposed the design and synthesis of a new class of BIR2 selective inhibitors of XIAP and their application in the development of new bivalent IAPs inhibitors. In addition, a new class of PROTACs which can be used to induce the ubiquitination of its target proteins have also been designed based upon these BIR2 selective IAPs inhibitors. These compounds will be studied for their mechanism of function, and if successfully carrying out, this project has the potential to lead to the identification of novel candidates for clinical studies.