大多数小分子药物都是通过与靶点蛋白的结合抑制其功能而达到治疗效果，但是免疫调节类药物，包括来那度胺、泊马度胺等利用glutarimide环结构劫持CRL4(CRBN)泛素连接酶促进骨髓瘤细胞生存所依赖的底物的泛素化降解而发挥治疗作用。为了发现更多的这种“分子胶水”，我们通过将不同的化学基团连接在固定的glutarimide环上，合成了152个化合物，并找出了依赖CRBN选择性杀伤肿瘤细胞的化合物106。通过质谱技术，我们发现106诱导G2-M检验点调控蛋白WEE1的降解。这里我们的研究目标如下：1）阐明WEE1是否是化合物106介导的CRL4(CRBN)泛素连接酶的底物；2）阐明WEE1的降解与化合物106细胞毒性的关系；3）在体内和体外验证化合物106与DNA损伤剂协同杀死癌症细胞的作用和机制。

Small molecule drugs typically occupy the binding sites of their target proteins to block protein functions and achieve therapeutic efficacy. By contrast, immunomodulatory drugs including lenalidomide and pomalidomide hijack the CRL4(CRBN) ubiquitin ligase with their glutarimide ring to degrade substrates essential for myeloma cell survival. To discover more such “molecular glues”, we synthesized a library of 152 compounds with diverse chemical moieties fixed to a glutarimide ring, and identified a compound 106 (cpd106) with CRBN-dependent cytotoxicity in selected cancer types. By mass spectrometry analysis, we found that cpd106 induced the proteasomal turnover of WEE1, a G2/M checkpoint kinase in cell cycle. Here we propose to test the following aims: 1) demonstrate that WEE1 is a cpd106-dependent substrate of CRL4(CRBN); 2) determine the role of WEE1 degradation in cpd106-induced cytotoxicity; 3) explore the synergy of cpd106 and DNA-damage agents in cancer inhibition in vitro and in vivo.