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
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（7）
• 所属期刊栏目: Anti-tumor Pharmacology
• 页码范围: 1160-1170
• 页数: 11页
• 语种: 英文

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(2.5-20μM)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.