Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer

作者全名："Pu, Chunlan; Tong, Yu; Liu, Yuanyuan; Lan, Suke; Wang, Shirui; Yan, Guoyi; Zhang, Hongjia; Luo, Dan; Ma, Xinyu; Yu, Su; Huang, Qing; Deng, Rui; Li, Rui"

作者地址："[Pu, Chunlan; Liu, Yuanyuan; Wang, Shirui; Zhang, Hongjia; Luo, Dan; Ma, Xinyu; Yu, Su; Huang, Qing; Deng, Rui; Li, Rui] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Pu, Chunlan; Liu, Yuanyuan; Wang, Shirui; Zhang, Hongjia; Luo, Dan; Ma, Xinyu; Yu, Su; Huang, Qing; Deng, Rui; Li, Rui] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China; [Pu, Chunlan] Chongqing Med Univ, Southwest Jiaotong Univ, Chengdu Hosp 2, Med Res Ctr,Peoples Hosp Chengdu 3,Affiliated Hos, Chengdu 610031, Sichuan, Peoples R China; [Tong, Yu] Sichuan Univ, Minist Educ, West China Univ Hosp 2, Key Lab Birth Defects & Related Dis Women & Child, Chengdu, Sichuan, Peoples R China; [Lan, Suke] Southwest Minzu Univ, Coll Chem & Environm Protect Engn, Chengdu, Sichuan, Peoples R China; [Yan, Guoyi] Xinxiang Univ, Sch Pharm, Xinxiang 4453000, Henan, Peoples R China"

通信作者："Li, R (通讯作者)，Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.; Li, R (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China."

来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000793653100004

JCR分区：Q1

影响因子：6.7

年份：2022

卷号：236

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：DCAF16; PROTACs; Degradation of PARP2; Monotherapy; Triple-negative breast cancer

摘要："Triple negative breast cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC. Herein, we describe a novel PROTACs C8, which was obtained by conjugating PARP1/2 inhibitor Olaparib to KB02, can induce potent and specific degradation of PARP2 by recruiting DCAF16 E3 ligase for treatment of wild-type TNBC. Moreover, C8 exhibits therapeutic potential in TNBC cell lines MDA-MB-231 both in vitro and in vivo. These studies demonstrated that the DCAF16 E3 ligases can be used in PARP2 PROTACs design, and C8, as a novel PARP2 selective DCAF16 based PROTACs, might be a promising lead compound for the treatment of BRCA-wild-type TNBC. (c) 2022 Elsevier Masson SAS. All rights reserved."

基金机构：National Natural Science Foundation of China [81773195]; Sichuan Science and Technology Program [2021YJ0220]

基金资助正文：We thank all members of this study for helpful discussion throughout experimentation. We would like to thank the Analytical & Testing Center of Sichuan University for NMR and HRMS spectra test work. This work was supported by National Natural Science Foundation of China (81773195) and Sichuan Science and Technology Program 2021YJ0220.