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

Xiao-bing Chen1, Hai-ying Zhu1, Kun Bao2, Li Jiang1, Hong Zhu1, Mei-dan Ying1, Qiao-jun He1,3, Bo Yang1,3, Rong Sheng2, Ji Cao1,3
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 and 4Cancer Center of Zhejiang University, Hangzhou 310058, China
Correspondence to: Bo Yang:, Rong Sheng:,
DOI: 10.1038/s41401-020-00600-5
Received: 21 April 2020
Accepted: 16 December 2020
Advance online: 25 January 2021


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.
Keywords: DJ-1 inhibitor; DM10; isatin derivatives; homodimer; anticancer therapy; apoptosis; ferroptosis; STK793590

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