Bis-isatin derivatives: design, synthesis, and biological activity evaluation as potent dimeric DJ-1 inhibitors  

作　　者：Xiao-bing Chen Hai-ying Zhu Kun Bao Li Jiang Hong Zhu Mei-dan Ying Qiao-jun He Bo Yang Rong Sheng Ji Cao 

机构地区：[1]Institute of Pharmacology and Toxicology,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [2]ZJU-ENS Joint Laboratory of Medicinal Chemistry,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [3]Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou 310058,China [4]Cancer Center of Zhejiang University,Hangzhou 310058,China

出　　处：《Acta Pharmacologica Sinica》2021年第7期1160-1170,共11页中国药理学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(No.81773757 to MDY,No.81402951 to JC);the National Science Technology Major Project"Key New Drug Creation and Manufacturing Program/China(2018ZX09711002-003-008 to HZ);and the Zhejiang Provincial Natural Science Foundation(No.Y18H310005 to JC).

摘　　要：The PARK7 gene (encode DJ-1 protein) was first discovered as an oncogene and later found to be a causative gene for autosomal recessive early onset Parkinson’s disease. DJ-1 has been proposed as a potential therapeutic anticancer target due to its pivotal role in tumorigenesis and cancer progression. Based on the homodimer structure of DJ-1, a series of bis-isatin derivatives with different length linkers were designed, synthesized, and evaluated as dimeric inhibitors targeting DJ-1 homodimer. Among them, DM10 with alkylene chain of C10 displayed the most potent inhibitory activity against DJ-1 deglycase. We further demonstrated that DM10 bound covalently to the homodimer of DJ-1. In human cancer cell lines H1299, MDA-MB-231, BEL7402, and 786-O, DM10 (2.5–20 μM) inhibited the cell growth in a concentration-dependent manner showing better anticancer effects compared with the positive control drug STK793590. In nude mice bearing H1299 cell xenograft, intratumor injection of DM10 (15 mg/kg) produced significantly potent tumor growth inhibition when compared with that caused by STK793590 (30 mg/kg). Moreover, we found that DM10 could significantly enhance N-(4-hydroxyphenyl)retinamide-based apoptosis and erastin-based ferroptosis in H1299 cells. In conclusion, DM10 is identified as a potent inhibitor targeting DJ-1 homodimer with the potential as sensitizing agent for other anticancer drugs, which might provide synergistical therapeutic option for cancer treatment.

关 键 词：DJ-1 inhibitor DM10 isatin derivatives HOMODIMER anticancer therapy apoptosis ferroptosis STK793590 

分 类 号：R96[医药卫生—药理学]