机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.[3]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.[4]Institute of Immunology and Inflammation,Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[5]Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China.
The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound 10e potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.
基金：
Xuejiao Song (West China School of Public
Health and West China Fourth Hospital, Sichuan University).
This work was supported by National S&T Major Special Project on Major New Drug Innovations (2018ZX09201018)
and National Base for International Science and Technology
Cooperation of Chengdu University (ISTC202203).
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, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Wan Guoquan,Feng Zhanzhan,Zhang Qiangsheng,et al.Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer[J].Journal of medicinal chemistry.2022,doi:10.1021/acs.jmedchem.2c01413.
APA：
Wan Guoquan,Feng Zhanzhan,Zhang Qiangsheng,Li Xiao,Ran Kai...&Yu Luoting.(2022).Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer.Journal of medicinal chemistry,,
MLA：
Wan Guoquan,et al."Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer".Journal of medicinal chemistry .(2022)
医学