Developing selective PI3K degraders to modulate both kinase and non-kinase functions  

作　　者：Zimo Yang Yan Tong Yongbo Liu Qianlong Liu Zhihao Ni Yuna He Yu Rao 

机构地区：[1]State Key Laboratory of Molecular Oncology,MOE Key Laboratory of Protein Sciences,MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology,School of Pharmaceutical Sciences,Tsinghua University,Beijing 100084,China

出　　处：《Chinese Chemical Letters》2024年第11期384-388,共5页中国化学快报（英文版）

基　　金：supported by National Key R&D Program of China(Nos.2021YFA1302100,2021YFA1300200,2020YFE0202200);National Natural Science Foundation of China(Nos.82125034,82330115)。

摘　　要：For the first time,proteolysis-targeting chimeras(PROTAC)technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases(PI3Ks)in this study.Through screening and optimization,the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110αin multiple breast cancer cells.More importantly,the degrader can down-regulate p85 regulatory subunit simultaneously,thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110catalytic subunits.Therefore,compared with PI3K inhibitor copanlisib,ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells.In brief,a selective and efficient PROTAC molecule was developed to induce the degradation of p110αand concurrent reduction of p85 proteins,providing a tool compound for the biological study of PI3K-αby blocking its enzymatic and non-enzymatic functions.

关 键 词：PI3K PROTAC p110 P85 SELECTIVITY Degradation Non-kinase functions 

分 类 号：Q55[生物学—生物化学]