机构：[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.四川大学华西医院[2]Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163 Tennessee, United States.[3]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.四川大学华西医院
A novel series of hybrid molecules combining pyrrolobenzodiazepine (PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized, and tested for in vitro cytotoxicity against various cancer cell lines. The most potent compound from this series, 37b3, exhibited a subnanomolar level of cytotoxicity with an IC50 of 0.17-0.94 nM. 37b3 induced DNA damage and led to tumor cell cycle arrest and apoptosis. We employed 37b3 as a payload to conjugate with trastuzumab to obtain the antibody-drug conjugate (ADC) T-PBA. T-PBA maintained its mode of target and internalization ability of trastuzumab. We demonstrated that T-PBA could be degraded through the lysosomal pathway to release the payload 37b3 after internalization. T-PBA showed a powerful killing effect on Her2-positive cancer cells in vitro. Furthermore, T-PBA significantly inhibited tumor growth in gastric and ovarian cancer xenograft mouse models without overt toxicity. Collectively, these studies suggest that T-PBA represents a promising new ADC that deserves further investigation.
基金：
This study was supported by grants from the National Natural
Science Foundation of China (82073318, 81872907), the
China Postdoctoral Science Foundation (2020M683336), the
Sichuan Science and Technology Program (2019YFS0003),
the CAMS Innovation Fund for Medical Sciences (CIFMS)
(2021-I2M-5-075), and the National Major Scientific and
Technological Special Project for Significant New Drugs
Development (2018ZX09201018-021, 2017ZX09302010).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.[3]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.[*1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China[*2]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China[*3]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
推荐引用方式(GB/T 7714)：
Lai Weirong,Zhao Shengyan,Lai Qinhuai,et al.Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate[J].Journal of medicinal chemistry.2022,doi:10.1021/acs.jmedchem.2c00471.
APA：
Lai Weirong,Zhao Shengyan,Lai Qinhuai,Zhou Wei,Wu Mengdan...&Yang Jinliang.(2022).Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate.Journal of medicinal chemistry,,
MLA：
Lai Weirong,et al."Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate".Journal of medicinal chemistry .(2022)
医学