Ferroptosis-centered Drug Response Information
General Information of the Drug (ID: ferrodrug0433)
| Name |
QD394
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| Drug Type |
Small molecule
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Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
| In total 1 item(s) under this Target | |||||
| Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target | [1] | ||||
| Target for Ferroptosis | Suppressor | ||||
| Responsed Disease | Pancreatic cancer | ICD-11: 2C10 | |||
| Pathway Response | Fatty acid metabolism | hsa01212 | |||
| Ferroptosis | hsa04216 | ||||
| Cell Process | Cell ferroptosis | ||||
| In Vitro Model | MIA PaCa-2 cells | Pancreatic ductal adenocarcinoma | Homo sapiens | CVCL_0428 | |
| PANC-1 cells | Pancreatic ductal adenocarcinoma | Homo sapiens | CVCL_0480 | ||
| BxPC-3 cells | Pancreatic ductal adenocarcinoma | Homo sapiens | CVCL_0186 | ||
| In Vivo Model |
Female Balb/c mice were purchased from Envigo. At the time of implantation, all mice were aged 5-6 weeks. Mice were implanted subcutaneously in the right flank with 1 x 106 CT-26 cells in 100 uL DPBS. Seven days after implantation, mice were randomized into groups (n = 5) with mean tumor volumes ranging from 97 to 117 mm3. The negative control group was dosed daily in the intraperitoneal cavity (IP) with the same vehicle used for QD394. QD394 was dosed at 10 mg/kg IP, and QD394-Me was dosed 3 times weekly intravenously (IV) at 20 mg/kg.
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| Response regulation | QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer. | ||||