Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy.
机构：[1]State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Joint Research Institution of Altitude Health, West China Hospital of Sichuan University, Chengdu 610041, Sichuan,China.四川大学华西医院[2]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan,China.四川大学华西医院
The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound BP44 with high selectivity for BRD4 and PARP1. Fortunately, BP44 inhibits the homologous recombination in triple-negative breast cancer (TNBC) and triggers synthetic lethality, thus leading to cell cycle arrest and DNA damage. In conclusion, we optimized the BRD4-PARP1 inhibitor based on previous studies, and we expect it to become a candidate drug for the treatment of TNBC in the future. This strategy aims to expand the use of PARPi in BRCA-competent TNBC, making an innovative approach to address unmet oncology needs.
基金：
We gratefully acknowledge for the technical assistance of Core
Facility of West China Hospital (L.C., Y.L., and X.X.). This
work was supported by the National Natural Science
Foundation of China (Grant Numbers 81922064, 81874290,
and 81903502), and the Fundamental Research Funds for the
Central Universities (Grant Number 2021SCU12102).
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, National Clinical Research Center for Geriatrics, Joint Research Institution of Altitude Health, West China Hospital of 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, National Clinical Research Center for Geriatrics, Joint Research Institution of Altitude Health, West China Hospital of Sichuan University, Chengdu 610041, Sichuan,China.[*1]State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Joint Research Institution of Altitude Health, West China Hospital of Sichuan University, Chengdu 610041 Sichuan, China
推荐引用方式(GB/T 7714)：
Zhang Jifa,Yang Chengcan,Tang Pan,et al.Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy.[J].Journal of medicinal chemistry.2022,65(9):6803-6825.doi:10.1021/acs.jmedchem.2c00135.
APA：
Zhang Jifa,Yang Chengcan,Tang Pan,Chen Juncheng,Zhang Dan...&Ouyang Liang.(2022).Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy..Journal of medicinal chemistry,65,(9)
MLA：
Zhang Jifa,et al."Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy.".Journal of medicinal chemistry 65..9(2022):6803-6825
医学