Azacoccone E inhibits cancer cell growth by targeting 3-phosphoglycerate dehydrogenase |
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| Institution: | 1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;2. Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China;2. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People''s Republic of China;2. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People''s Republic of China;3. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People''s Republic of China;4. Department of Pharmacy, The Central Hospital of Wuhan Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People''s Republic of China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People''s Republic of China;2. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People''s Republic of China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China;2. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;2. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China |
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| Abstract: | Serine plays critically important roles in tumorigenesis. Homo sapiens 3-phosphoglycerate dehydrogenase (PHGDH) catalyzes the first committed step for the synthesis of glucose-derived serine via the phosphoserine pathway and has been associated with a wide variety of cancers, including breast cancer, melanoma, colon cancer, glioma, nasopharyngeal carcinoma, cervical adenocarcinoma, etc. Azacoccone E, an aza-epicoccone derivative from the culture of Aspergillus flavipes, exhibited effective inhibitory activity against PHGDH in vitro. The microscale thermophoresis (MST) method and the cellular thermal shift assay (CETSA) confirmed that azacoccone E directly bound to PHGDH. And the cell-based experiments showed that this compound was selectively toxic to PHGDH-dependent cancer cells and could cause apoptosis. Further biochemical assays revealed that it was a noncompetitive inhibitor with respect to the substrate of 3-PG and exhibited a time-dependent inhibition. Furthermore, molecular docking demonstrated that azacoccone E coordinated in an allosteric site of PHGDH with low binding energy. Therefore, azacoccone E can be considered as a possible drug candidate targeting at PHGDH for treatment of cancers. |
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| Keywords: | Azacoccone E PHGDH inhibitor Natural product Cancer |
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