Related Experiment Video
Updated: Nov 20, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Bis-isatin derivatives: design, synthesis, and biological activity evaluation as potent dimeric DJ-1 inhibitors
Xiao-Bing Chen1, Hai-Ying Zhu1, Kun Bao2
1Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
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.
Insights
A novel DJ-1 homodimer inhibitor, DM10, effectively suppressed cancer cell growth and xenograft tumors. DM10 also enhanced apoptosis and ferroptosis, showing potential as a synergistic cancer therapy agent.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- The PARK7 gene, encoding DJ-1 protein, is implicated in tumorigenesis and cancer progression.
- DJ-1 is a validated therapeutic target for anticancer drug development.
- DJ-1's homodimer structure offers a unique target for inhibitor design.
Purpose of the Study:
- To design, synthesize, and evaluate novel bis-isatin derivatives as DJ-1 homodimer inhibitors.
- To assess the anticancer efficacy of the lead compound DM10 in vitro and in vivo.
- To investigate DM10's potential as a sensitizing agent for other anticancer drugs.
Main Methods:
- Synthesis of bis-isatin derivatives with varying linker lengths.
- In vitro enzymatic assays to determine DJ-1 deglycase inhibitory activity.
- Cell viability assays in multiple human cancer cell lines (H1299, MDA-MB-231, BEL7402, 786-O).
- In vivo efficacy study using H1299 cell xenografts in nude mice.
- Assessment of DM10's effect on apoptosis and ferroptosis induction.
Main Results:
- DM10, a C10 linker derivative, exhibited potent DJ-1 deglycase inhibition and covalently bound to the DJ-1 homodimer.
- DM10 significantly inhibited cancer cell growth in a dose-dependent manner, outperforming the positive control STK793590.
- Intratumoral injection of DM10 demonstrated potent tumor growth inhibition in a xenograft model.
- DM10 enhanced N-(4-hydroxyphenyl)retinamide-induced apoptosis and erastin-induced ferroptosis in H1299 cells.
Conclusions:
- DM10 is a potent DJ-1 homodimer inhibitor with significant anticancer activity.
- DM10 demonstrates potential as a sensitizing agent, enhancing the efficacy of other anticancer drugs.
- DM10 offers a promising synergistic therapeutic strategy for cancer treatment.
Related Concept Videos
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
01:28Stability of Conjugated Dienes
A comparison of the enthalpies of hydrogenation of dienes reveals that conjugated dienes release less heat on hydrogenation, rendering them more stable than their nonconjugated analogs.