Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

作     者：Ziqi Huang Kun Zhang Yurui Jiang Mengmeng Wang Mei Li Yuda Guo Ruolin Gao Ning Li Chenyang Wang Jia Chen Jiefu Wang Ning Liu Xiang Liu Shuangwei Liu Mingming Wei Cheng Yang Guang Yang 

作者机构：The State Key Laboratory of Medicinal Chemical BiologyCollege of Life SciencesCollege of PharmacyNankai UniversityTianjin 300071China Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第9期

页      面：4001-4013页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100101[医学-人体解剖与组织胚胎学] 10[医学] 

基　　金：the National Natural Science Foundation of China(NSFC,No.82003186,82073691 and 82373134) the International Science and Technology Cooperation Project of China(No.2022YFE0133300) Ningbo Science and Technology Bureau under CM2025 Programme(2020Z092,China) Shenzhen Science and Technology Foundation(JCYJ20210324122006017,China) Tianjin Natural Science Fund(21JCQNJC01910,China) China Postdoctoral Science Foundation e Tianjin Joint Support Program(No.2023T029TJ) 

主　　题：Molecular glue Targeted protein degradation PHGDH Cancer stem cells PROTACs 

摘      要：Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and ***,targeting CSCs has emerged as a promising avenue for cancer ***,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem ***,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are *** this study,the novel“molecular glueLXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in ***,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 *** insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH ***,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.