Development of the non-receptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness
2023-05
发表期刊JOURNAL OF BIOLOGICAL CHEMISTRY (IF:4.0[JCR-2023],4.4[5-Year])
ISSN0021-9258
发表状态已发表
DOI10.1016/j.jbc.2023.104825
摘要

Aberrant overexpression of non-receptor tyrosine kinase FER has been reported in a variety of ovarian carcinoma-derived tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell migration and invasion, acting concurrently in both kinase-dependent and -independent manners, which is not easily suppressed by conventional enzymatic inhibitors. Nevertheless, the proteolysis-targeting chimeras (PROTACs) technology offers a superior efficacy over conventional activity-based inhibitors by targeting both enzymatic and scaffold functions simultaneously. Hence in this study, we report the development of two PROTAC compounds that promote robust FER degradation in a cereblon-dependent manner. Both PROTAC degraders outperform an FDA-approved drug, Brigatinib, in ovarian cancer cell motility suppression. Importantly, these PROTAC compounds also degrade multiple oncogenic FER fusion proteins identified in human tumor samples. These results lay an experimental foundation to apply the PROTAC strategy to antagonize metastasis in ovarian and other types of cancers with aberrant expression of FER kinase and highlight PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions.

关键词Protein degradation PROTAC Tyrosine kinase FER Ovarian cancer
收录类别SCI
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/331104
专题生命科学与技术学院
生命科学与技术学院_PI研究组_范高峰组
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
通讯作者Xiaobao Yang; Dake Li; Gaofeng Fan
作者单位
1.School of Life Science and Technology, ShanghaiTech University, Shanghai, China
2.Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai, China
3.Department of Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
第一作者单位生命科学与技术学院
通讯作者单位生命科学与技术学院
第一作者的第一单位生命科学与技术学院
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Yanchun Zhang,Xuexue Xiong,Renhong Sun,et al. Development of the non-receptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2023.
APA Yanchun Zhang.,Xuexue Xiong.,Renhong Sun.,Xiaotong Zhu.,Chen Wang.,...&Gaofeng Fan.(2023).Development of the non-receptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness.JOURNAL OF BIOLOGICAL CHEMISTRY.
MLA Yanchun Zhang,et al."Development of the non-receptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness".JOURNAL OF BIOLOGICAL CHEMISTRY (2023).
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